Code Description CPT
0012U Germline disorders, gene rearrangement detection by whole genome next-generation sequencing, DNA, whole blood, report of specific gene rearrangement(s)
81415 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis
81416 Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure)
81417 Exome (eg, unexplained constitutional or heritable disorder or syndrome); reevaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome)
81425 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis
81426 Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure)
81427 Genome (eg, unexplained constitutional or heritable disorder or syndrome); reevaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome)
81479 Unlisted molecular pathology code
Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders
Introduction
Our DNA contains all of our genetic material, and makes us who we are. Our DNA contains about 20,000 genes which are packaged into 46 chromosomes (23 pairs). Genes are very important because they tell our cells how to make proteins. Although there are tens of thousands of genes, they make up only about 1% of our entire DNA. A large part of our DNA doesn’t code for any proteins. The protein-coding genes are also called “exomes”.
The entire collection of DNA is called the “whole genome”. If a person was only talking about the genes themselves that are contained within the whole genome, they are called the “whole exome”.
“Whole genome sequencing” is a test that looks at the entire genome, including parts of the DNA that don’t contain any genes. “Whole exome sequencing” is a test that only looks at the exomes, which is that part of the DNA that contains genes that code for proteins. As an analogyan entire football game would be your whole genome. Only the game highlights (1% of the game) would be the exomes. Whole genome sequencing would be like watching the entire football game from start to finish, while whole exome sequencing would be like watching only the game highlights the next day.
Whole genome and whole exome sequencing tests have been used to help diagnose genetic disorders in people. Whole genome sequencing is always considered to be investigational. Not enough good quality medical studies have been done to show that whole genome sequencing is reliable and helpful in diagnosing genetic conditions. However, whole exome sequencing may be medically necessary in some situations. This policy describes when whole exome sequencing may be medically necessary.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Policy Coverage Criteria
The policy statement is intended to address the use of whole exome and whole genome sequencing for the diagnosis of genetic disorders in patients with suspected genetic disorders and for population-based screening.
This policy does not address the use of whole exome and whole genome sequencing for preimplantation genetic diagnosis or screening, prenatal (fetal) testing, or testing of cancer cells.
Service Medical Necessity
Whole exome sequencing Whole exome sequencing may be considered medically necessary for the evaluation of unexplained congenital or neurodevelopmental disorders in children under the age of 18 when ALL of the following criteria are met: ? The patient has been evaluated by a clinician with expertise in
clinical genetics and counseled about the potential risks of genetic testing.
AND ? There is potential for a change in management and clinical
outcome for the individual being tested. AND ? A genetic etiology is felt to be the most likely explanation for
the patient’s signs and symptoms despite previous genetic testing (eg, chromosomal microarray analysis and/or targeted single-gene testing), OR when previous genetic testing has
Service Medical Necessity failed to yield a diagnosis, and the affected individual is faced with invasive procedures or testing as the next diagnostic step (eg, muscle biopsy).
Whole exome sequencing is considered investigational for the diagnosis of genetic disorders in all other situations. Service Investigational
Whole genome sequencing Whole genome sequencing is considered investigational for the diagnosis of genetic disorders.
Whole exome sequencing Whole genome sequencing
Coding
Whole exome sequencing and whole genome sequencing are considered investigational for screening of asymptomatic individuals for genetic disorders.
Whole Exome Sequencing (WES)
Whole Exome Sequencing (WES) is proven and medically necessary for diagnosing or evaluating a genetic disorder when the results are expected to directly influence medical management and clinical outcomes AND ALL of the following criteria are met:
** Clinical presentation is nonspecific and does not fit a well-defined syndrome for which a specific or targeted gene test is available. If a specific genetic syndrome is suspected, a single gene or targeted gene panel should be performed prior to determining if WES is necessary; and
** WES is ordered by a board-certified medical geneticist, neonatologist, neurologist, or developmental and behavioral pediatrician; and
** One of the following:
* The clinical presentation or clinical and family history strongly suggest a genetic cause for which a specific clinical diagnosis cannot be made with any clinically available targeted genetic tests; or
* There is a clinical diagnosis of a genetic condition where there is significant genetic heterogeneity and WES is a more practical approach to identifying the underlying genetic cause than are individual tests of multiple genes; or
* There is likely a genetic disorder and multiple targeted gene tests that have failed to identify the underlying cause.
Comparator (e.g., parents or siblings) WES is proven and medically necessary for evaluating a genetic disorder when the above criteria have been met and WES is performed concurrently or has been previously performed on the individual.
WES is unproven and not medically necessary for all other indications, including but not limited to the following:
** Screening and evaluating disorders in individuals when the above criteria are not met
** Prenatal genetic diagnosis or screening
** Evaluation of fetal demise
** Preimplantation Genetic Testing (PGT) in embryos
** Molecular profiling of tumors for the diagnosis, prognosis or management of cancer
Further studies are needed to evaluate the clinical utility of whole exome sequencing for other indications.
Whole Genome Sequencing (WGS)
Whole Genome Sequencing (WGS) is unproven and not medically necessary for screening and evaluating any genetic disorder. Although WGS has the potential to identify causal variants for a wide variety of conditions that may be missed with other technologies, as well as to identify predictive biomarkers, the information derived from WGS has not yet been translated into improved outcomes and changed medical management. Further studies are needed to establish the clinical utility of WGS.
DEFINITIONS
Comparator: A DNA sequence that is used to compare to the individual’s DNA sequence. This may be a parent or sibling of the individual, or non-cancerous tissue that is being compared to the individual’s tumor tissue (Thun et al., 2017).
Next Generation Sequencing (NGS): New sequencing techniques that can quickly analyze multiple sections of DNA at the same time. Older forms of sequencing could only analyze one section of DNA at once. Preimplantation Genetic Testing (PGT): A test performed to analyze the DNA from oocytes or embryos for human leukocyte antigen (HLA)-typing or for determining genetic abnormalities. These include:
* PGT-A: For aneuploidy screening (formerly PGS)
** PGT-M: For monogenic/single gene defects (formerly single-gene PGD)
** PGT-SR: For chromosomal structural rearrangements (formerly chromosomal PGD)(Zegers-Hochschild et al., 2017)
Variant of Unknown Significance (VUS): A variation in a genetic sequence that has an unknown association with disease. It may also be called an unclassified variant. Whole Exome Sequencing (WES): About 1% of a person’s DNA makes protein. These protein making sections are called exons. All the exons together are called the exome. WES is a DNA analysis technique that looks at all of the exons in a person at one time, rather than gene by gene (U.S. National Library of Medicine, What are whole exome sequencing and whole genome sequencing? 2018).
Whole Genome Sequencing (WGS): WGS determines the sequence of all of the DNA in a person, which includes the protein making (coding) as well as non-coding DNA elements (U.S. National Library of Medicine, What are whole exome sequencing and whole genome sequencing? 2018).
Appropriate Use Criteria
Whole Exome Sequencing
Whole exome sequencing (WES) (81415 and 81416) is medically necessary for a phenotypicallyaffected individual when all of the following criteria are met: • Individual has been evaluated by a board-certified medical geneticist or other boardcertified specialist physician with specific expertise in the conditions being tested for and relevant genes
• WES results will directly impact clinical decision-making and/or clinical outcome
• A genetic etiology is the most likely explanation for the phenotype as demonstrated by the following:
• Multiple abnormalities affecting unrelated organ systems
or two of the following four criteria:
• Abnormality affecting a single organ system
• Significant intellectual disability or severe psychological/psychiatric disturbance (e.g. self-injurious behavior, reversed sleep-wake cycles)
• Family history strongly implicating a genetic etiology
• Period of unexplained developmental regression (unrelated to autism or epilepsy)
• No other causative circumstances (e.g. environmental exposures, injury, infection) can explain symptoms
• Clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available
• The differential diagnosis list and/or phenotype warrant testing of multiple genes, and at least one of the following:
* WES is more practical than the separate single gene tests or panels that would be recommended based on the differential diagnosis
* WES results may preclude the need for multiple and/or invasive procedures, follow-up, or screening that would be recommended in the absence of testing
Friday, July 5, 2019
Friday, June 14, 2019
CPT 81223, 81401, 81404 - Genetic Testing for Hereditary Pancreatitis
Code Description CPT
81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence
81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)
Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V,R122H)
81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence, SPINK1 (serine peptidase inhibitor, Kazal type 1) (eg, hereditary pancreatitis), full gene sequence
81479 Unlisted molecular pathology
Genetic Testing for Hereditary Pancreatitis
Introduction
The pancreas is an important organ behind and below the stomach. It releases enzymes to help us digest our food and also releases hormones (insulin and glucagon) to help the body control how it uses the food for energy. If the pancreas becomes inflamed, it is called pancreatitis. In some people, pancreatitis may have come on suddenly and only lasts for a short time (acute pancreatitis). Other people may have been sick with pancreatitis for a long time (chronic pancreatitis). Chronic pancreatitis may seem to run in some families, and as a result these cases may be caused by genetic problems. Genetic testing has sometimes been done to see if a person has hereditary pancreatitis. This policy discusses when genetic testing for hereditary pancreatitis may be medically necessary.
Testing Medical Necessity
Genetic testing for hereditary pancreatitis
Genetic testing for hereditary pancreatitis may be considered medically necessary for patients aged 18 years and younger with unexplained recurrent (greater than 1 episode) acute or chronic pancreatitis with documented elevated amylase or lipase levels.
Related Information
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Consideration of Age
The age described in this policy for medical necessity of genetic testing for hereditary pancreatitis is age 18 and younger. Having recurrent pancreatitis in children is not very common. The literature regarding genetic testing for hereditary pancreatitis in children is sparse. Although there is a lot of evidence, there is consensus opinion from physician medical societies that, in children with more than one episode of pancreatitis, a positive result of this genetic testing may make additional invasive testing unnecessary. See the Evidence Review section below for more detail.
Evidence Review
Description
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, diabetes mellitus, and increased risk for pancreatic cancer. Hereditary pancreatitis (HP) is a subset of CP defined clinically as a familial pattern of CP. Variants of several genes are associated with HP. Demonstration of a pathogenic genetic variant in one or several of these genes can potentially be used to confirm the diagnosis
of HP, provide information on prognosis and management, and/or determine the risk of CP in asymptomatic relatives of patients with HP.
Background Pancreatitis
Acute and chronic pancreatitis (CP) is caused by the premature activation of trypsinogen into trypsin within the pancreas, resulting in autodigestion, inflammation, increased levels of pancreatic enzymes in the serum, and abdominal pain. CP is defined as an ongoing inflammatory state associated with chronic/recurrent symptoms and progression to exocrine and endocrine pancreatic insufficiency.
Alcohol is the major etiologic factor in 80% of CP, which has a peak incidence in the fourth and fifth decades of life. Gall stones, hypercalcemia, inflammatory bowel disease, autoimmune pancreatitis, and peptic ulcer disease can also cause CP. About 20% of CP is idiopathic.
A small percentage of CP is categorized as hereditary pancreatitis (HP), which usually begins with recurrent episodes of acute pancreatitis in childhood and evolves into CP by age 20 years. Multiple family members may be affected over several generations, and pedigree analysis often reveals an autosomal dominant pattern of inheritance. Clinical presentation and family history alone are sometimes insufficient to distinguish between idiopathic CP and HP, especially early in the course of the disease. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.
Genetic Determinants of Hereditary Pancreatitis (HP)
PRSS1 Variant
Whitcomb (2001) discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen.
The gain of function variants of the PRSS1 gene cause HP by prematurely and excessively converting trypsinogen to trypsin, which results in pancreatic autodigestion. Between 60% and 80% of people who have a disease-associated PRSS1 variant will experience pancreatitis in their lifetimes; 30% to 40% will develop CP. Most, but not all, people with a disease-associated variant of PRSS1 will have inherited it from one of their parents. The proportion of HP caused by a de novo variant of PRSS1 is unknown. In families with 2 or more affected individuals in 2 or more generations, genetic testing has shown that most have a demonstrable disease-associated PRSS1 variant. In 60% to 100%, the variant is detected by sequencing technology (Sanger or next-generation), and duplications of exons or the whole PRSS1 gene are seen in about 6%. Two PRSS1 point variants (p.Arg122His, p.Asn29Ile) are most common, accounting for 90% of disease-associated variants in affected individuals. Over 40 other PRSS1 sequence variants have been found, but their clinical significance is uncertain. Pathogenic PRSS1 variants are present in 10% or less of individuals with CP.
Targeted analysis of exons 2 and 3, where the common disease-associated variants are found, or PRSS1 sequencing, are first-line tests, followed by duplication analysis. The general indications for PRSS1 testing and emphasis on pre- and post-test genetic counseling have remained central features of reviews and guidelines.
However, several other genes have emerged as significant contributors to both HP and CP. They include the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, serine peptidase inhibitor, Kazal type 1 (SPINK1) gene, chymotrypsin C (CTRC) gene, and claudin-2 (CLDN-2) gene.
CFTR Variants
Autosomal recessive variants of CFTR cause CF, a chronic disease with onset in childhood that causes severe sinopulmonary disease and numerous gastrointestinal abnormalities. The signs and symptoms of CF can vary widely. On rare occasions, an affected individual may have mild pulmonary disease, pancreatic exocrine sufficiency, and may present with acute, recurrent acute, or CP.
Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR variants (homozygotes or compound heterozygotes) will benefit from CF-specific evaluations, therapies, and genetic counseling.
SPINK Variants
The SPINK gene encodes a protein that binds to trypsin and thereby inhibits its activity. Variants in SPINK are not associated with acute pancreatitis but are found, primarily as modifiers, in recurrent acute pancreatitis and seem to promote the development of CP, including for individuals with compound heterozygous variants of the CFTR gene. Autosomal recessive familial pancreatitis may be caused by homozygous or compound heterozygous SPINK variants.
CTRC Variants
CTRC is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W and p.K247_R254del) are associated with an increased risk for idiopathic CP (odds ratio [OR], 4.6), alcoholic pancreatitis (OR =4.2), and tropical pancreatitis (OR =13.6).
CLDN2 Variants
CLDN2 encodes a member of the claudin protein family, which acts as an integral membrane protein at tight junctions and has tissue-specific expression. Several single nucleotide polymorphisms in CLDN2 have been associated with CP.
Genetic Testing for Variants
Testing for variants associated with HP is typically done by direct sequence analysis or nextgeneration sequencing (NGS). A number of laboratories offer testing for the relevant genes, either individually or as panels. For example, ARUP Laboratories (Salt Lake City, UT) offers a Pancreatitis Panel, which includes direct (Sanger) sequencing of CFTR, CTRC, PRSS1, and SPINK.
Prevention Genetics (Marshfield, WI) offers a Chronic Pancreatitis Sequencing Panel, which includes NGS of 5 genes: CASR, CFTR, CTRC, PRSS1, and SPINK1.
Ambry Genetics (Aliso Viejo, CA) offers a Pancreatitis Panel, which includes NGS of PRSS1, SPINK1, CTRC, and CFTR.
Ambry’s PancNext™ panel for variants associated with increased risk of pancreatic cancer consists of NGS of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53.
Clinical Policy: Carrier Screening in Pregnancy
Description
This policy outlines medical necessity criteria for cystic fibrosis (CF) and spinal muscular atrophy (SMA) carrier testing.
Policy/Criteria
I. It is the policy of health plans affiliated with Centene Corporation® that CF carrier screening (CPT® code 81220) or SMA carrier screening (81401) is medically necessary for women who are pregnant and meet the following criteria:
A. No prior CF or SMA screening results are available, and
B. Pregnancy ≤ 22 weeks gestation, and
C. Underwent pretest counseling.
II. It is the policy of Centene Corporation that CF or SMA carrier screening anytime other than during pregnancy and for requests for CF screening CPT® codes 81221 – 81224 during pregnancy is medically necessary when meeting the most current version of the relevant nationally recognized decision support tools
Authorization Protocols
Requests for prior authorization will be accepted up to 5 business days after specimen collection and reviewed for medical necessity based on the above stated criteria.
CLINICAL POLICY Carrier Screening in Pregnancy
If both parents are carriers, chorionic villus sampling or amniocentesis can be performed to see whether the fetus has the disease. Since these are both invasive procedures that carry a slight risk to the fetus, further testing should only be performed if and when the course of the pregnancy will be altered based on results of the testing.
CPT Codes Description
81220 CFTR (cystic fibrosis transmembrane conductance regulator (eg. Cystic fibrosis) gene analysis; common variants (eg. ACMG/ACOG guidelines)
81221 known family variants
81222 Duplication/deletion variants
81223 Full gene sequence
81224 Intron 8 poly-T analysis (eg, male infertility)
81401 Molecular pathology procedure level 2 (used for SMA carrier testing)
Documentation Guidelines
Documentation must be adequate to verify that coverage guidelines listed above have been met. Thus, the medical record must contain documentation that the testing is expected to influence treatment of the condition toward which the testing is directed. The laboratory or billing provider must have on file the physician requisition which sets forth the diagnosis or condition that warrants the test(s).
Examples of documentation requirements of the ordering physician/nonphysician practitioner (NPP) include, but are not limited to, history and physical or exam findings that support the decision making, problems/diagnoses, relevant data (e.g., lab testing, imaging results).
Documentation requirements of the performing laboratory (when requested) include, but are not limited to, lab accreditation, test requisition, test record/procedures, reports (preliminary and final), and quality control record.
Documentation requirements for lab developed tests/protocols (when requested) include diagnostic test/assay, lab/manufacturer, names of comparable assays/services (if relevant), description of assay, analytical validity evidence, clinical validity evidence, and clinical utility.
Providers are required to code to specificity however, if an unlisted CPT code is used the documentation must clearly identify the unique procedure performed. When multiple procedure codes are submitted on a claim (unique and/or unlisted) the documentation supporting each code should be easily identifiable. If on review the contractor cannot link a billed code to the documentation, these services will be denied based on Title XVIII of the Social Security Act,
§1833(e).
When the documentation does not meet the criteria for the service rendered or the documentation does not establish the medical necessity for the services, such services will be denied as not reasonable and necessary under Section 1862(a)(1)(A) of the Social Security Act.
81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence
81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)
Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V,R122H)
81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
Includes the following tests: PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence, SPINK1 (serine peptidase inhibitor, Kazal type 1) (eg, hereditary pancreatitis), full gene sequence
81479 Unlisted molecular pathology
Genetic Testing for Hereditary Pancreatitis
Introduction
The pancreas is an important organ behind and below the stomach. It releases enzymes to help us digest our food and also releases hormones (insulin and glucagon) to help the body control how it uses the food for energy. If the pancreas becomes inflamed, it is called pancreatitis. In some people, pancreatitis may have come on suddenly and only lasts for a short time (acute pancreatitis). Other people may have been sick with pancreatitis for a long time (chronic pancreatitis). Chronic pancreatitis may seem to run in some families, and as a result these cases may be caused by genetic problems. Genetic testing has sometimes been done to see if a person has hereditary pancreatitis. This policy discusses when genetic testing for hereditary pancreatitis may be medically necessary.
Testing Medical Necessity
Genetic testing for hereditary pancreatitis
Genetic testing for hereditary pancreatitis may be considered medically necessary for patients aged 18 years and younger with unexplained recurrent (greater than 1 episode) acute or chronic pancreatitis with documented elevated amylase or lipase levels.
Related Information
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Consideration of Age
The age described in this policy for medical necessity of genetic testing for hereditary pancreatitis is age 18 and younger. Having recurrent pancreatitis in children is not very common. The literature regarding genetic testing for hereditary pancreatitis in children is sparse. Although there is a lot of evidence, there is consensus opinion from physician medical societies that, in children with more than one episode of pancreatitis, a positive result of this genetic testing may make additional invasive testing unnecessary. See the Evidence Review section below for more detail.
Evidence Review
Description
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, diabetes mellitus, and increased risk for pancreatic cancer. Hereditary pancreatitis (HP) is a subset of CP defined clinically as a familial pattern of CP. Variants of several genes are associated with HP. Demonstration of a pathogenic genetic variant in one or several of these genes can potentially be used to confirm the diagnosis
of HP, provide information on prognosis and management, and/or determine the risk of CP in asymptomatic relatives of patients with HP.
Background Pancreatitis
Acute and chronic pancreatitis (CP) is caused by the premature activation of trypsinogen into trypsin within the pancreas, resulting in autodigestion, inflammation, increased levels of pancreatic enzymes in the serum, and abdominal pain. CP is defined as an ongoing inflammatory state associated with chronic/recurrent symptoms and progression to exocrine and endocrine pancreatic insufficiency.
Alcohol is the major etiologic factor in 80% of CP, which has a peak incidence in the fourth and fifth decades of life. Gall stones, hypercalcemia, inflammatory bowel disease, autoimmune pancreatitis, and peptic ulcer disease can also cause CP. About 20% of CP is idiopathic.
A small percentage of CP is categorized as hereditary pancreatitis (HP), which usually begins with recurrent episodes of acute pancreatitis in childhood and evolves into CP by age 20 years. Multiple family members may be affected over several generations, and pedigree analysis often reveals an autosomal dominant pattern of inheritance. Clinical presentation and family history alone are sometimes insufficient to distinguish between idiopathic CP and HP, especially early in the course of the disease. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.
Genetic Determinants of Hereditary Pancreatitis (HP)
PRSS1 Variant
Whitcomb (2001) discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen.
The gain of function variants of the PRSS1 gene cause HP by prematurely and excessively converting trypsinogen to trypsin, which results in pancreatic autodigestion. Between 60% and 80% of people who have a disease-associated PRSS1 variant will experience pancreatitis in their lifetimes; 30% to 40% will develop CP. Most, but not all, people with a disease-associated variant of PRSS1 will have inherited it from one of their parents. The proportion of HP caused by a de novo variant of PRSS1 is unknown. In families with 2 or more affected individuals in 2 or more generations, genetic testing has shown that most have a demonstrable disease-associated PRSS1 variant. In 60% to 100%, the variant is detected by sequencing technology (Sanger or next-generation), and duplications of exons or the whole PRSS1 gene are seen in about 6%. Two PRSS1 point variants (p.Arg122His, p.Asn29Ile) are most common, accounting for 90% of disease-associated variants in affected individuals. Over 40 other PRSS1 sequence variants have been found, but their clinical significance is uncertain. Pathogenic PRSS1 variants are present in 10% or less of individuals with CP.
Targeted analysis of exons 2 and 3, where the common disease-associated variants are found, or PRSS1 sequencing, are first-line tests, followed by duplication analysis. The general indications for PRSS1 testing and emphasis on pre- and post-test genetic counseling have remained central features of reviews and guidelines.
However, several other genes have emerged as significant contributors to both HP and CP. They include the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, serine peptidase inhibitor, Kazal type 1 (SPINK1) gene, chymotrypsin C (CTRC) gene, and claudin-2 (CLDN-2) gene.
CFTR Variants
Autosomal recessive variants of CFTR cause CF, a chronic disease with onset in childhood that causes severe sinopulmonary disease and numerous gastrointestinal abnormalities. The signs and symptoms of CF can vary widely. On rare occasions, an affected individual may have mild pulmonary disease, pancreatic exocrine sufficiency, and may present with acute, recurrent acute, or CP.
Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR variants (homozygotes or compound heterozygotes) will benefit from CF-specific evaluations, therapies, and genetic counseling.
SPINK Variants
The SPINK gene encodes a protein that binds to trypsin and thereby inhibits its activity. Variants in SPINK are not associated with acute pancreatitis but are found, primarily as modifiers, in recurrent acute pancreatitis and seem to promote the development of CP, including for individuals with compound heterozygous variants of the CFTR gene. Autosomal recessive familial pancreatitis may be caused by homozygous or compound heterozygous SPINK variants.
CTRC Variants
CTRC is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W and p.K247_R254del) are associated with an increased risk for idiopathic CP (odds ratio [OR], 4.6), alcoholic pancreatitis (OR =4.2), and tropical pancreatitis (OR =13.6).
CLDN2 Variants
CLDN2 encodes a member of the claudin protein family, which acts as an integral membrane protein at tight junctions and has tissue-specific expression. Several single nucleotide polymorphisms in CLDN2 have been associated with CP.
Genetic Testing for Variants
Testing for variants associated with HP is typically done by direct sequence analysis or nextgeneration sequencing (NGS). A number of laboratories offer testing for the relevant genes, either individually or as panels. For example, ARUP Laboratories (Salt Lake City, UT) offers a Pancreatitis Panel, which includes direct (Sanger) sequencing of CFTR, CTRC, PRSS1, and SPINK.
Prevention Genetics (Marshfield, WI) offers a Chronic Pancreatitis Sequencing Panel, which includes NGS of 5 genes: CASR, CFTR, CTRC, PRSS1, and SPINK1.
Ambry Genetics (Aliso Viejo, CA) offers a Pancreatitis Panel, which includes NGS of PRSS1, SPINK1, CTRC, and CFTR.
Ambry’s PancNext™ panel for variants associated with increased risk of pancreatic cancer consists of NGS of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53.
Clinical Policy: Carrier Screening in Pregnancy
Description
This policy outlines medical necessity criteria for cystic fibrosis (CF) and spinal muscular atrophy (SMA) carrier testing.
Policy/Criteria
I. It is the policy of health plans affiliated with Centene Corporation® that CF carrier screening (CPT® code 81220) or SMA carrier screening (81401) is medically necessary for women who are pregnant and meet the following criteria:
A. No prior CF or SMA screening results are available, and
B. Pregnancy ≤ 22 weeks gestation, and
C. Underwent pretest counseling.
II. It is the policy of Centene Corporation that CF or SMA carrier screening anytime other than during pregnancy and for requests for CF screening CPT® codes 81221 – 81224 during pregnancy is medically necessary when meeting the most current version of the relevant nationally recognized decision support tools
Authorization Protocols
Requests for prior authorization will be accepted up to 5 business days after specimen collection and reviewed for medical necessity based on the above stated criteria.
CLINICAL POLICY Carrier Screening in Pregnancy
If both parents are carriers, chorionic villus sampling or amniocentesis can be performed to see whether the fetus has the disease. Since these are both invasive procedures that carry a slight risk to the fetus, further testing should only be performed if and when the course of the pregnancy will be altered based on results of the testing.
CPT Codes Description
81220 CFTR (cystic fibrosis transmembrane conductance regulator (eg. Cystic fibrosis) gene analysis; common variants (eg. ACMG/ACOG guidelines)
81221 known family variants
81222 Duplication/deletion variants
81223 Full gene sequence
81224 Intron 8 poly-T analysis (eg, male infertility)
81401 Molecular pathology procedure level 2 (used for SMA carrier testing)
Documentation Guidelines
Documentation must be adequate to verify that coverage guidelines listed above have been met. Thus, the medical record must contain documentation that the testing is expected to influence treatment of the condition toward which the testing is directed. The laboratory or billing provider must have on file the physician requisition which sets forth the diagnosis or condition that warrants the test(s).
Examples of documentation requirements of the ordering physician/nonphysician practitioner (NPP) include, but are not limited to, history and physical or exam findings that support the decision making, problems/diagnoses, relevant data (e.g., lab testing, imaging results).
Documentation requirements of the performing laboratory (when requested) include, but are not limited to, lab accreditation, test requisition, test record/procedures, reports (preliminary and final), and quality control record.
Documentation requirements for lab developed tests/protocols (when requested) include diagnostic test/assay, lab/manufacturer, names of comparable assays/services (if relevant), description of assay, analytical validity evidence, clinical validity evidence, and clinical utility.
Providers are required to code to specificity however, if an unlisted CPT code is used the documentation must clearly identify the unique procedure performed. When multiple procedure codes are submitted on a claim (unique and/or unlisted) the documentation supporting each code should be easily identifiable. If on review the contractor cannot link a billed code to the documentation, these services will be denied based on Title XVIII of the Social Security Act,
§1833(e).
When the documentation does not meet the criteria for the service rendered or the documentation does not establish the medical necessity for the services, such services will be denied as not reasonable and necessary under Section 1862(a)(1)(A) of the Social Security Act.
Friday, May 24, 2019
CPT 81504, 86849 - Multiple myeloma, Microarray based Gene testing
Coding Code Description CPT
81479 Unlisted molecular pathology procedure
81504 Oncology (tissue of origin), microarray gene expression profiling of >2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores
81599 Unlisted multianalyte assay with algorithmic analysis (MAAA)
86849 Unlisted immunology procedure
Microarray-Based Gene Expression Profile Testing for Multiple Myeloma Risk Stratification
Introduction
Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell. Doctors aren’t sure what causes multiple myeloma. Abnormal changes (mutations) in genes have been found in the plasma cells of people who have multiple myeloma. Not everyone with multiple myeloma has the same genetic changes in their plasma cells, and some genetic changes seem to make the cancer more deadly than others. It has been suggested that a type of testing called “microarray-based gene expression profiling” can be used to try to determine the prognosis of an individual’s multiple myeloma. Not enough good quality medical studies have been done to show that this type of testing is reliable and helpful in taking care of multiple myeloma patients. For this reason, microarray-based gene expression profiling is still considered to be unproven (investigational).
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Policy Coverage Criteria
Testing Investigational
Microarray-based gene expression profile testing
Microarray-based gene expression profile testing for multiple myeloma is considered investigational for all indications.
Note: Commercially available tests include MyPRS™/MyPRS Plus™ GEP70 test.
See Related Information for a key to acronyms used in this policy.
Related Information
Acronym Key
CRAB: This stands for the four clinical features of multiple myeloma: calcium elevation; renal insufficiency; anemia; and, bone disease.
DSS: This stands for Durie-Salmon Staging System. One of the two validated clinical system used to assess prognosis in newly diagnosed multiple myeloma patients. The DSS estimates the clinical stage (stage range is 1-3) of disease by assessing multiple myeloma cell numbers, clinical, laboratory and imaging studies. The DSS is primarily focused on tumor mass, rather than tumor behavior. (See ISS system)
GEP: This stands for gene expression profile. GEP testing measures the activity of messenger RNA (mRNA) in a tissue or bodily fluid at a single point, reflecting an individual’s current disease state or the likelihood of developing a disease. GEP tests are not “genetic” tests.
ISS: This stands for the International Staging System. One of the two validated clinical systems used to assess prognosis in patients newly diagnosed with multiple myeloma. The ISS divides myeloma into 3 stages based on levels of serum albumin and ß2-microglobulin in the blood. The ISS is considered valuable to permit comparison of outcomes across clinical trials, but can only be useful if diagnosis has already been made. (See DSS system).
MGUS: This stands for monoclonal gammopathy of undetermined significance. MGUS is a generally benign condition, with a transformation rate to symptomatic plasma cell disorders (like multiple myeloma) of about 1% to 2% annually.
MolDx: ResponseDX Tissue of Origin® Billing and Coding Guidelines
Tissue of Origin®, a microarray-based gene expression assay designed to determine the similarity of unknown or unresolved tumors to cancers from 1 of 15 known tumors of origin, has been assigned a unique identifier.
To bill for Tissue of Origin services, please provide the following claim information:
• Enter “1” in the Days/Unit field
• Select the appropriate ICD-10-CM diagnosis.
• Enter DEX Z-Code™ identifier adjacent to the CPT code in the comment/narrative field for the following
Part B claim field/types:
◦ Loop 2400 or SV101-7 for the 5010A1 837P
◦ Box 19 for paper claim
• Enter DEX Z-Code™ identifier adjacent to the CPT code in the comment/narrative field for the following Part A claim field/types:
◦ Line SV202-7 for 837I electronic claim
◦ Block 80 for the UB04 claim form
Group 1 Codes:
ICD-10 Codes that are covered Information Table
Code Description
C18.1 Malignant neoplasm of appendix
C18.9 Malignant neoplasm of colon, unspecified
C22.0 Liver cell carcinoma
C22.2 Hepatoblastoma
C22.3 Angiosarcoma of liver
C22.4 Other sarcomas of liver
C22.7 Other specified carcinomas of liver
C22.8 Malignant neoplasm of liver, primary, unspecified as to type
C22.9 Malignant neoplasm of liver, not specified as primary or secondary
C25.2 Malignant neoplasm of tail of pancreas
C25.7 Malignant neoplasm of other parts of pancreas
C25.8 Malignant neoplasm of overlapping sites of pancreas
C25.9 Malignant neoplasm of pancreas, unspecified
C33 Malignant neoplasm of trachea
C34.00 Malignant neoplasm of unspecified main bronchus
C34.01 Malignant neoplasm of right main bronchus
C34.02 Malignant neoplasm of left main bronchus
C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung
C34.11 Malignant neoplasm of upper lobe, right bronchus or lung
C34.12 Malignant neoplasm of upper lobe, left bronchus or lung
C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung
C34.31 Malignant neoplasm of lower lobe, right bronchus or lung
C34.32 Malignant neoplasm of lower lobe, left bronchus or lung
C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung
C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung
C34.92 Malignant neoplasm of unspecified part of left bronchus or lung
C43.51 Malignant melanoma of anal skin
C43.52 Malignant melanoma of skin of breast
C43.59 Malignant melanoma of other part of trunk
C45.9 Mesothelioma, unspecified
C47.0 Malignant neoplasm of peripheral nerves of head, face and neck
C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified
C48.0 Malignant neoplasm of retroperitoneum
C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck
C49.9 Malignant neoplasm of connective and soft tissue, unspecified
C50.411 Malignant neoplasm of upper-outer quadrant of right female breast
C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast
C50.511 Malignant neoplasm of lower-outer quadrant of right female breast
C50.512 Malignant neoplasm of lower-outer quadrant of left female breast
C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast
C50.811 Malignant neoplasm of overlapping sites of right female breast
C50.812 Malignant neoplasm of overlapping sites of left female breast
C50.819 Malignant neoplasm of overlapping sites of unspecified female breast
C50.911 Malignant neoplasm of unspecified site of right female breast
C50.912 Malignant neoplasm of unspecified site of left female breast
C50.919 Malignant neoplasm of unspecified site of unspecified female breast
C56.1 Malignant neoplasm of right ovary
C56.2 Malignant neoplasm of left ovary
C56.9 Malignant neoplasm of unspecified ovary
C61 Malignant neoplasm of prostate
C64.1 Malignant neoplasm of right kidney, except renal pelvis
Microarray-based Gene Expression Testing for Cancers of Unknown Primary
Policy Guidelines
Cancers of unknown primary (CUP) represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment accordingly may improve health outcomes.
For individuals who have a CUP who receive gene expression profiling, the evidence includes studies of clinical validity, and limited evidence on potential clinical utility. Relevant outcomes are overall survival, disease-specific survival, test validity, and quality of life. Of the 3 commercially available tests reviewed, one has been cleared by the Food and Drug Administration (Tissue of Origin). For these tests, the clinical validity is the ability of a test to determine the site of origin. Using different reference standards (known tumor type, reference diagnosis, a primary tumor identified during follow-up, immunohistochemical analysis) for the tissue of origin, the tests have reported sensitivities or concordances generally high (eg, 80% to 90% or more). However, evidence for clinical validity does not support potential benefit. There is limited indirect evidence from nonrandomized studies on clinical utility, and all studies had significant limitations. Benefit would be most convincingly demonstrated through a marker strategy-designed trial randomizing patients with a CUP to treatment based on expression profiling results or to usual care. The evidence is insufficient to determine the effects of the technology on health outcomes.
Billing/Coding/Physician Documentation Information
This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.
Applicable service codes: 81479, 81504, 81540, G0452
BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.
81479 Unlisted molecular pathology procedure
81504 Oncology (tissue of origin), microarray gene expression profiling of >2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores
81599 Unlisted multianalyte assay with algorithmic analysis (MAAA)
86849 Unlisted immunology procedure
Microarray-Based Gene Expression Profile Testing for Multiple Myeloma Risk Stratification
Introduction
Multiple myeloma is a cancer that forms in a type of white blood cell called a plasma cell. Doctors aren’t sure what causes multiple myeloma. Abnormal changes (mutations) in genes have been found in the plasma cells of people who have multiple myeloma. Not everyone with multiple myeloma has the same genetic changes in their plasma cells, and some genetic changes seem to make the cancer more deadly than others. It has been suggested that a type of testing called “microarray-based gene expression profiling” can be used to try to determine the prognosis of an individual’s multiple myeloma. Not enough good quality medical studies have been done to show that this type of testing is reliable and helpful in taking care of multiple myeloma patients. For this reason, microarray-based gene expression profiling is still considered to be unproven (investigational).
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Policy Coverage Criteria
Testing Investigational
Microarray-based gene expression profile testing
Microarray-based gene expression profile testing for multiple myeloma is considered investigational for all indications.
Note: Commercially available tests include MyPRS™/MyPRS Plus™ GEP70 test.
See Related Information for a key to acronyms used in this policy.
Related Information
Acronym Key
CRAB: This stands for the four clinical features of multiple myeloma: calcium elevation; renal insufficiency; anemia; and, bone disease.
DSS: This stands for Durie-Salmon Staging System. One of the two validated clinical system used to assess prognosis in newly diagnosed multiple myeloma patients. The DSS estimates the clinical stage (stage range is 1-3) of disease by assessing multiple myeloma cell numbers, clinical, laboratory and imaging studies. The DSS is primarily focused on tumor mass, rather than tumor behavior. (See ISS system)
GEP: This stands for gene expression profile. GEP testing measures the activity of messenger RNA (mRNA) in a tissue or bodily fluid at a single point, reflecting an individual’s current disease state or the likelihood of developing a disease. GEP tests are not “genetic” tests.
ISS: This stands for the International Staging System. One of the two validated clinical systems used to assess prognosis in patients newly diagnosed with multiple myeloma. The ISS divides myeloma into 3 stages based on levels of serum albumin and ß2-microglobulin in the blood. The ISS is considered valuable to permit comparison of outcomes across clinical trials, but can only be useful if diagnosis has already been made. (See DSS system).
MGUS: This stands for monoclonal gammopathy of undetermined significance. MGUS is a generally benign condition, with a transformation rate to symptomatic plasma cell disorders (like multiple myeloma) of about 1% to 2% annually.
MolDx: ResponseDX Tissue of Origin® Billing and Coding Guidelines
Tissue of Origin®, a microarray-based gene expression assay designed to determine the similarity of unknown or unresolved tumors to cancers from 1 of 15 known tumors of origin, has been assigned a unique identifier.
To bill for Tissue of Origin services, please provide the following claim information:
• Enter “1” in the Days/Unit field
• Select the appropriate ICD-10-CM diagnosis.
• Enter DEX Z-Code™ identifier adjacent to the CPT code in the comment/narrative field for the following
Part B claim field/types:
◦ Loop 2400 or SV101-7 for the 5010A1 837P
◦ Box 19 for paper claim
• Enter DEX Z-Code™ identifier adjacent to the CPT code in the comment/narrative field for the following Part A claim field/types:
◦ Line SV202-7 for 837I electronic claim
◦ Block 80 for the UB04 claim form
Group 1 Codes:
ICD-10 Codes that are covered Information Table
Code Description
C18.1 Malignant neoplasm of appendix
C18.9 Malignant neoplasm of colon, unspecified
C22.0 Liver cell carcinoma
C22.2 Hepatoblastoma
C22.3 Angiosarcoma of liver
C22.4 Other sarcomas of liver
C22.7 Other specified carcinomas of liver
C22.8 Malignant neoplasm of liver, primary, unspecified as to type
C22.9 Malignant neoplasm of liver, not specified as primary or secondary
C25.2 Malignant neoplasm of tail of pancreas
C25.7 Malignant neoplasm of other parts of pancreas
C25.8 Malignant neoplasm of overlapping sites of pancreas
C25.9 Malignant neoplasm of pancreas, unspecified
C33 Malignant neoplasm of trachea
C34.00 Malignant neoplasm of unspecified main bronchus
C34.01 Malignant neoplasm of right main bronchus
C34.02 Malignant neoplasm of left main bronchus
C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung
C34.11 Malignant neoplasm of upper lobe, right bronchus or lung
C34.12 Malignant neoplasm of upper lobe, left bronchus or lung
C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung
C34.31 Malignant neoplasm of lower lobe, right bronchus or lung
C34.32 Malignant neoplasm of lower lobe, left bronchus or lung
C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung
C34.81 Malignant neoplasm of overlapping sites of right bronchus and lung
C34.92 Malignant neoplasm of unspecified part of left bronchus or lung
C43.51 Malignant melanoma of anal skin
C43.52 Malignant melanoma of skin of breast
C43.59 Malignant melanoma of other part of trunk
C45.9 Mesothelioma, unspecified
C47.0 Malignant neoplasm of peripheral nerves of head, face and neck
C47.9 Malignant neoplasm of peripheral nerves and autonomic nervous system, unspecified
C48.0 Malignant neoplasm of retroperitoneum
C49.0 Malignant neoplasm of connective and soft tissue of head, face and neck
C49.9 Malignant neoplasm of connective and soft tissue, unspecified
C50.411 Malignant neoplasm of upper-outer quadrant of right female breast
C50.419 Malignant neoplasm of upper-outer quadrant of unspecified female breast
C50.511 Malignant neoplasm of lower-outer quadrant of right female breast
C50.512 Malignant neoplasm of lower-outer quadrant of left female breast
C50.519 Malignant neoplasm of lower-outer quadrant of unspecified female breast
C50.811 Malignant neoplasm of overlapping sites of right female breast
C50.812 Malignant neoplasm of overlapping sites of left female breast
C50.819 Malignant neoplasm of overlapping sites of unspecified female breast
C50.911 Malignant neoplasm of unspecified site of right female breast
C50.912 Malignant neoplasm of unspecified site of left female breast
C50.919 Malignant neoplasm of unspecified site of unspecified female breast
C56.1 Malignant neoplasm of right ovary
C56.2 Malignant neoplasm of left ovary
C56.9 Malignant neoplasm of unspecified ovary
C61 Malignant neoplasm of prostate
C64.1 Malignant neoplasm of right kidney, except renal pelvis
Microarray-based Gene Expression Testing for Cancers of Unknown Primary
Policy Guidelines
Cancers of unknown primary (CUP) represent 3% to 4% of cancers diagnosed in the United States. These cancers are heterogeneous and many accompanied by poor prognoses. A detailed history and physical combined with imaging and tissue pathology can identify some, but not all, primary sources of secondary tumors. It is suggested that identifying the likely primary source with gene expression profiling to direct treatment accordingly may improve health outcomes.
For individuals who have a CUP who receive gene expression profiling, the evidence includes studies of clinical validity, and limited evidence on potential clinical utility. Relevant outcomes are overall survival, disease-specific survival, test validity, and quality of life. Of the 3 commercially available tests reviewed, one has been cleared by the Food and Drug Administration (Tissue of Origin). For these tests, the clinical validity is the ability of a test to determine the site of origin. Using different reference standards (known tumor type, reference diagnosis, a primary tumor identified during follow-up, immunohistochemical analysis) for the tissue of origin, the tests have reported sensitivities or concordances generally high (eg, 80% to 90% or more). However, evidence for clinical validity does not support potential benefit. There is limited indirect evidence from nonrandomized studies on clinical utility, and all studies had significant limitations. Benefit would be most convincingly demonstrated through a marker strategy-designed trial randomizing patients with a CUP to treatment based on expression profiling results or to usual care. The evidence is insufficient to determine the effects of the technology on health outcomes.
Billing/Coding/Physician Documentation Information
This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.
Applicable service codes: 81479, 81504, 81540, G0452
BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.
Thursday, April 4, 2019
CPT 81324, 81325, 81326, 81448 - Genetic testing
Coding Code Description CPT
81324 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis
81325 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis
81326 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant
81448 Hereditary peripheral neuropathies (eg, Charcot-Marie-Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes (eg, BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, SPTLC1) (new code effective 1/1/18)
Introduction
Neuropathy is a term related to disease or damage to nerves. Peripheral neuropathy refers to nerve disorders that affect the nerves leaving the spinal cord and going out to the body, often those nerves in the arms and legs. These neuropathies may be due to damage to nerves related to certain other conditions such as diabetes, or inflammatory or immune problems. Rarely a peripheral nerve problem is inherited and occurs in families. In these conditions genetic changes can be passed from parent to child. The most common inherited peripheral neuropathy is Charcot-Marie-Tooth (CMT) syndrome. There are different forms of CMT that result in weakness and muscles wasting away. CMT usually affects muscles in the foot, lower leg, hand, and forearm. Another type of inherited peripheral neuropathy is hereditary neuropathy with liability to pressure palsies (HNPP). In HNPP people experience numbness or tingling when there’s pressure on, or injury to a nerve. This sensation can last for a few minutes to days or months. CMT and HNPP are both uncommon and can usually be diagnosed with a physical exam. This policy discusses when genetic testing for inherited peripheral neuropathies may be medically necessary.
Policy Coverage Criteria
Testing Medical Necessity
Genetic testing
Genetic testing for suspected but undiagnosed Charcot-Marie- Tooth (CMT) Syndrome may be considered medically necessary in the following setting: * Weakness on exam of foot, leg or hand and/or deformities or decreased ability to walk or manipulate items with hands AND * Electromyogram (EMG) and/or nerve conduction tests (NCT) are non-diagnostic Genetic testing for suspected but undiagnosed hereditary neuropathy with liability to pressure palsies (HNPP) may be considered medically necessary in the following setting: * Person with transient compression neuropathy which may include pain, numbness or weakness AND * EMG and/or NCT have been non-diagnostic Testing Investigational
Genetic testing Genetic testing for an inherited peripheral or sensory neuropathy is considered investigational for all other indications not outlined above.
Related Information
This policy addresses the hereditary motor and sensory peripheral neuropathies, of which peripheral neuropathy is the primary clinical manifestation. A number of other hereditary disorders may have neuropathy as an associated finding but typically have other central nervous system and occasionally other systemic findings. Examples include Refsum disease, various lysosomal storage diseases, and mitochondrial disorders.
Definition of Terms
Charcot-Marie-Tooth (CMT) neuropathy: This inherited disease is a group of progressive disorders that affect the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect touch, pain, heat and sound. Damage to the peripheral nerves can result in loss of sensation and wasting (atrophy) of muscles in the arms and legs. This is also known as peroneal muscular atrophy, or progressive neural muscular atrophy or hereditary motor and sensory neuropathy.
Hereditary neuropathy with liability to pressure palsies (HNPP): This is a slowly progressive disorder affecting peripheral nerves. It is caused by deletions of the PMP22 gene that instructs the body to make a protein (ie, peripheral myelin protein 22) that plays a crucial role in the production and maintenance of myelin in the peripheral nervous system. HNPP increases the probability of nerve injury from stretch, pressure or repetitive use. The injured nerves lose their insulating covering; added pressure causes pain, numbness, weakness or even paralysis in the area. The disorder may sometimes be diagnosed during a work-up for carpal tunnel syndrome or peroneal palsy.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
81324 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis
81325 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis
81326 PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant
81448 Hereditary peripheral neuropathies (eg, Charcot-Marie-Tooth, spastic paraplegia), genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes (eg, BSCL2, GJB1, MFN2, MPZ, REEP1, SPAST, SPG11, SPTLC1) (new code effective 1/1/18)
Introduction
Neuropathy is a term related to disease or damage to nerves. Peripheral neuropathy refers to nerve disorders that affect the nerves leaving the spinal cord and going out to the body, often those nerves in the arms and legs. These neuropathies may be due to damage to nerves related to certain other conditions such as diabetes, or inflammatory or immune problems. Rarely a peripheral nerve problem is inherited and occurs in families. In these conditions genetic changes can be passed from parent to child. The most common inherited peripheral neuropathy is Charcot-Marie-Tooth (CMT) syndrome. There are different forms of CMT that result in weakness and muscles wasting away. CMT usually affects muscles in the foot, lower leg, hand, and forearm. Another type of inherited peripheral neuropathy is hereditary neuropathy with liability to pressure palsies (HNPP). In HNPP people experience numbness or tingling when there’s pressure on, or injury to a nerve. This sensation can last for a few minutes to days or months. CMT and HNPP are both uncommon and can usually be diagnosed with a physical exam. This policy discusses when genetic testing for inherited peripheral neuropathies may be medically necessary.
Policy Coverage Criteria
Testing Medical Necessity
Genetic testing
Genetic testing for suspected but undiagnosed Charcot-Marie- Tooth (CMT) Syndrome may be considered medically necessary in the following setting: * Weakness on exam of foot, leg or hand and/or deformities or decreased ability to walk or manipulate items with hands AND * Electromyogram (EMG) and/or nerve conduction tests (NCT) are non-diagnostic Genetic testing for suspected but undiagnosed hereditary neuropathy with liability to pressure palsies (HNPP) may be considered medically necessary in the following setting: * Person with transient compression neuropathy which may include pain, numbness or weakness AND * EMG and/or NCT have been non-diagnostic Testing Investigational
Genetic testing Genetic testing for an inherited peripheral or sensory neuropathy is considered investigational for all other indications not outlined above.
Related Information
This policy addresses the hereditary motor and sensory peripheral neuropathies, of which peripheral neuropathy is the primary clinical manifestation. A number of other hereditary disorders may have neuropathy as an associated finding but typically have other central nervous system and occasionally other systemic findings. Examples include Refsum disease, various lysosomal storage diseases, and mitochondrial disorders.
Definition of Terms
Charcot-Marie-Tooth (CMT) neuropathy: This inherited disease is a group of progressive disorders that affect the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect touch, pain, heat and sound. Damage to the peripheral nerves can result in loss of sensation and wasting (atrophy) of muscles in the arms and legs. This is also known as peroneal muscular atrophy, or progressive neural muscular atrophy or hereditary motor and sensory neuropathy.
Hereditary neuropathy with liability to pressure palsies (HNPP): This is a slowly progressive disorder affecting peripheral nerves. It is caused by deletions of the PMP22 gene that instructs the body to make a protein (ie, peripheral myelin protein 22) that plays a crucial role in the production and maintenance of myelin in the peripheral nervous system. HNPP increases the probability of nerve injury from stretch, pressure or repetitive use. The injured nerves lose their insulating covering; added pressure causes pain, numbness, weakness or even paralysis in the area. The disorder may sometimes be diagnosed during a work-up for carpal tunnel syndrome or peroneal palsy.
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Saturday, March 9, 2019
CPT 81252, 81253, 81254, 81430, 81431 - Genetic Testing for Hereditary Hearing Loss
Code Description CPT
81252 GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (eg, nonsyndromic hearing loss) gene analysis, full gene sequence
81253 GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants
81254 GJB6 (gap junction protein, beta 6, 30kDa, connexin 30)(eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)])
81430 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1
81431 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes
Genetic Testing for Hereditary Hearing Loss
Introduction
Hearing loss can be caused by illness, injuries, or even certain medications. A baby who is born too soon or who needs to use a breathing machine (ventilator) after birth may develop hearing loss. Complicating this even more is that hearing loss can be “syndromic.” This means that a person has other symptoms in addition to hearing loss. “Nonsyndromic” hearing loss means a person doesn’t have any other symptoms.
Genetic changes are the root cause of some hearing loss. If more than one person in a family has hearing loss, it is called familial hearing loss. Even in families with genetic hearing loss, it may not be caused by changes to any of the genes known to be associated with hearing. This policy describes when genetic testing for hearing loss may be considered medically necessary.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Genetic Testing Medical Necessity
Variants in hereditary hearing loss genes
Preconception genetic testing for hereditary hearing loss variants
Genetic testing for hereditary hearing loss genes (GJB2, GJB6, and other hereditary hearing loss-related genes) in individuals with suspected hearing loss in order to confirm the diagnosis of hereditary hearing loss (see Related Information) may be considered medically necessary.
Preconception genetic testing (carrier testing) for hereditary hearing loss gene (GJB2, GJB6, and other hereditary hearing loss-related genes) in parents may be considered medically necessary when at least one of the following conditions has been met: * Offspring with hereditary hearing loss OR * One or both parents with suspected hereditary hearing loss OR * First- or second-degree relative affected with hereditary
hearing loss OR * First-degree relative with offspring who is affected with
hereditary hearing loss
Genetic Testing Investigational
Variants in hereditary hearing loss genes
Related Information
Hereditary hearing loss can be classified as syndromic or nonsyndromic. The definition of nonsyndromic hearing loss (NSHL) is hearing loss that is not associated with other physical signs and symptoms at the time of hearing loss presentation. It is differentiated from syndromic hearing loss, which is hearing loss associated with other signs and symptoms characteristic of a specific syndrome. Physical signs of a syndrome often include dysmorphic changes in the maxillofacial region and/or malformations of the external ears. Malfunction of internal organs may also be part of a syndrome. The physical signs can be subtle and easily missed on physical exam, therefore exclusion of syndromic findings is ideally done by an individual with expertise in identifying dysmorphic physical signs. The phenotypic presentation of NSHL varies, but generally involves the following features:
* Sensorineural hearing loss
* Mild to profound (more commonly) degree of hearing impairment
* Congenital onset
* Usually non-progressive
This policy primarily focuses on the use of genetic testing to identify a cause of suspected hereditary hearing loss. The diagnosis of syndromic hearing loss may be able to be made on the
basis of associated clinical findings. However, at the time of hearing loss presentation, associated clinical findings may not be apparent; furthermore, variants in certain genetic loci may cause both syndromic and nonsyndromic hearing loss. Given this overlap, the policy focuses on genetic testing for hereditary hearing loss more generally.
In addition to pathogenic variants in the GJB6 and GJB2 genes, there are many less common pathogenic variants found in other genes. They include: ACTG1, CDH23, CLDN14, COCH, COL11A2, DFNA5, DFNB31, DFNB59, ESPN, EYA4, GJB2, GJB6, KCNQ4, LHFPL5, MT-TS1, MYO15A, MYO6, MYO7A, OTOF, PCDH15, POU3F4, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, TRIOBP, USH1C, and WFS1 genes.
Targeted testing for variants associated with hereditary hearing loss should be confined to known pathogenic variants. While research studies using genome-wide associations have uncovered numerous single nucleotide variants and copy number variations associated with hereditary hearing loss, the clinical significance of these findings is unclear.
For carrier testing, outcomes are expected to be improved if parents alter their reproductive decision making as a result of genetic test results. This may occur through the use of preimplantation genetic testing in combination with in vitro fertilization. Other ways that prospective parents may alter their reproductive choices are to proceed with attempts at pregnancy, or to avoid attempts at pregnancy, based on carrier testing results.
Testing Strategy
Evaluation of a patient with suspected hereditary hearing loss should involve a careful physical exam and family history to assess for associated clinical findings that may point to a specific syndromic or nonsyndromic cause of hearing loss (eg, infectious, toxic, autoimmune, other causes). Consideration should also be given to temporal bone computed tomography scanning in cases of progressive hearing loss and to testing for cytomegalovirus (CMV) in infants with sensorineural hearing loss.
If there is no high suspicion for a specific hearing loss etiology, ideally the evaluation should occur in a step-wise fashion. About 50% of individuals with autosomal recessive hereditary hearing loss have pathogenic variants in the GJB2 gene. In the remainder of patients with apparent autosomal recessive hereditary hearing loss, numerous other genes are implicated. In autosomal dominant hereditary hearing loss, there is no single identifiable gene responsible for most cases. If there is suspicion for autosomal recessive congenital hearing loss, it would be reasonable to begin with testing of GJB2 and GJB6. If this is negative, screening for the other genes associated with hearing loss with a multigene panel would be efficient. An alternative strategy for suspected autosomal recessive or autosomal dominant hearing loss would be to obtain a multigene panel that includes GJB2 and GJB6 as a first step. Given the extreme heterogeneity in genetic causes of hearing loss, these 2 strategies may be considered reasonably equivalent.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant Classification Definition
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies
81252 GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (eg, nonsyndromic hearing loss) gene analysis, full gene sequence
81253 GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants
81254 GJB6 (gap junction protein, beta 6, 30kDa, connexin 30)(eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)])
81430 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS1
81431 Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes
Genetic Testing for Hereditary Hearing Loss
Introduction
Hearing loss can be caused by illness, injuries, or even certain medications. A baby who is born too soon or who needs to use a breathing machine (ventilator) after birth may develop hearing loss. Complicating this even more is that hearing loss can be “syndromic.” This means that a person has other symptoms in addition to hearing loss. “Nonsyndromic” hearing loss means a person doesn’t have any other symptoms.
Genetic changes are the root cause of some hearing loss. If more than one person in a family has hearing loss, it is called familial hearing loss. Even in families with genetic hearing loss, it may not be caused by changes to any of the genes known to be associated with hearing. This policy describes when genetic testing for hearing loss may be considered medically necessary.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Genetic Testing Medical Necessity
Variants in hereditary hearing loss genes
Preconception genetic testing for hereditary hearing loss variants
Genetic testing for hereditary hearing loss genes (GJB2, GJB6, and other hereditary hearing loss-related genes) in individuals with suspected hearing loss in order to confirm the diagnosis of hereditary hearing loss (see Related Information) may be considered medically necessary.
Preconception genetic testing (carrier testing) for hereditary hearing loss gene (GJB2, GJB6, and other hereditary hearing loss-related genes) in parents may be considered medically necessary when at least one of the following conditions has been met: * Offspring with hereditary hearing loss OR * One or both parents with suspected hereditary hearing loss OR * First- or second-degree relative affected with hereditary
hearing loss OR * First-degree relative with offspring who is affected with
hereditary hearing loss
Genetic Testing Investigational
Variants in hereditary hearing loss genes
Related Information
Hereditary hearing loss can be classified as syndromic or nonsyndromic. The definition of nonsyndromic hearing loss (NSHL) is hearing loss that is not associated with other physical signs and symptoms at the time of hearing loss presentation. It is differentiated from syndromic hearing loss, which is hearing loss associated with other signs and symptoms characteristic of a specific syndrome. Physical signs of a syndrome often include dysmorphic changes in the maxillofacial region and/or malformations of the external ears. Malfunction of internal organs may also be part of a syndrome. The physical signs can be subtle and easily missed on physical exam, therefore exclusion of syndromic findings is ideally done by an individual with expertise in identifying dysmorphic physical signs. The phenotypic presentation of NSHL varies, but generally involves the following features:
* Sensorineural hearing loss
* Mild to profound (more commonly) degree of hearing impairment
* Congenital onset
* Usually non-progressive
This policy primarily focuses on the use of genetic testing to identify a cause of suspected hereditary hearing loss. The diagnosis of syndromic hearing loss may be able to be made on the
basis of associated clinical findings. However, at the time of hearing loss presentation, associated clinical findings may not be apparent; furthermore, variants in certain genetic loci may cause both syndromic and nonsyndromic hearing loss. Given this overlap, the policy focuses on genetic testing for hereditary hearing loss more generally.
In addition to pathogenic variants in the GJB6 and GJB2 genes, there are many less common pathogenic variants found in other genes. They include: ACTG1, CDH23, CLDN14, COCH, COL11A2, DFNA5, DFNB31, DFNB59, ESPN, EYA4, GJB2, GJB6, KCNQ4, LHFPL5, MT-TS1, MYO15A, MYO6, MYO7A, OTOF, PCDH15, POU3F4, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, TRIOBP, USH1C, and WFS1 genes.
Targeted testing for variants associated with hereditary hearing loss should be confined to known pathogenic variants. While research studies using genome-wide associations have uncovered numerous single nucleotide variants and copy number variations associated with hereditary hearing loss, the clinical significance of these findings is unclear.
For carrier testing, outcomes are expected to be improved if parents alter their reproductive decision making as a result of genetic test results. This may occur through the use of preimplantation genetic testing in combination with in vitro fertilization. Other ways that prospective parents may alter their reproductive choices are to proceed with attempts at pregnancy, or to avoid attempts at pregnancy, based on carrier testing results.
Testing Strategy
Evaluation of a patient with suspected hereditary hearing loss should involve a careful physical exam and family history to assess for associated clinical findings that may point to a specific syndromic or nonsyndromic cause of hearing loss (eg, infectious, toxic, autoimmune, other causes). Consideration should also be given to temporal bone computed tomography scanning in cases of progressive hearing loss and to testing for cytomegalovirus (CMV) in infants with sensorineural hearing loss.
If there is no high suspicion for a specific hearing loss etiology, ideally the evaluation should occur in a step-wise fashion. About 50% of individuals with autosomal recessive hereditary hearing loss have pathogenic variants in the GJB2 gene. In the remainder of patients with apparent autosomal recessive hereditary hearing loss, numerous other genes are implicated. In autosomal dominant hereditary hearing loss, there is no single identifiable gene responsible for most cases. If there is suspicion for autosomal recessive congenital hearing loss, it would be reasonable to begin with testing of GJB2 and GJB6. If this is negative, screening for the other genes associated with hearing loss with a multigene panel would be efficient. An alternative strategy for suspected autosomal recessive or autosomal dominant hearing loss would be to obtain a multigene panel that includes GJB2 and GJB6 as a first step. Given the extreme heterogeneity in genetic causes of hearing loss, these 2 strategies may be considered reasonably equivalent.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA
Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant Classification Definition
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Genetic Testing for the Diagnosis of Inherited Peripheral Neuropathies
Saturday, February 16, 2019
CPT 81302, 81303, 81304, 81404, 81406 - Rett syndrome
Coding Code Description CPT
81302 MECP2 (methyl CpG binding protein 2)(eg, Rett syndrome) gene analysis; full sequence analysis
81303 MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; known familial variant
81304 MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants
81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)
81599 Unlisted multianalyte assay with algorithmic analysis
Introduction
Rett syndrome is a rare disorder of the nervous system that affects mostly girls. This disorder influences how the brain develops. A girl with Rett syndrome grows normally for about the first six to eighteen months. Then, noticeable changes develop. The child’s loses the muscle ability she had already developed, so activities like crawling, walking, or using the hands begin to diminish. (Some boys also develop Rett syndrome but because of their chromosomal makeup they die before birth or as early in infancy.) A genetic change (mutation) is responsible for Rett syndrome. But this genetic change usually isn’t inherited from a parent. It most often occurs by chance. Rett syndrome can’t be cured. However, treatments can be used to help manage symptoms and provide support. Such care is usually needed throughout life. A genetic test is available to see if a person has Rett syndrome. This policy describes when the genetic test may be considered medically necessary.
Service Medical Necessity
Genetic testing for Rett syndrome
Targeted genetic testing for a known familial Rett syndrome*associated variant
Genetic testing for Rett syndrome *associated genes (eg, MECP2, FOXG1, or CDKL5) may be considered medically necessary when the following criteria are met: * To establish a genetic diagnosis of Rett syndrome in a child
with developmental delay and signs/symptoms of Rett syndrome, when a definitive diagnosis cannot be made without genetic testing
Testing for that variant is medically necessary to determine carrier status of a mother or a sister of an individual with Rett syndrome.
Service Investigational
All other indications for genetic testing for Rett syndrome*associated genes
All other indications for genetic testing for Rett syndrome associated genes (eg, MECP2, FOXG1, or CDKL5) are considered investigational including: * Routine carrier testing (preconception or prenatal) in persons with negative family history of Rett syndrome AND * Testing of asymptomatic family members to determine future risk of the disease
Related Information
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Table 1. Nomenclature to Report on Variants Found in DNA Previous Updated Definition
Mutation Disease-associated variant Disease-associated change in the DNA sequence
Previous Updated Definition
Variant Change in the DNA sequence
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives
Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and the understanding of risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Evidence Review
Description
Rett syndrome (RTT), a neurodevelopmental disorder, is usually caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene. Genetic testing is available to determine
whether a pathogenic variant exists in RTT-associated genes (eg, MECP2, FOXG1, or CDLK5) in a patient with clinical features of RTT or a patient’s family member.
Background
Rett Syndrome
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls, with an incidence of 1 in 10,000 female births, making it among the most common genetic causes of intellectual disability in girls.
In its typical form, RTT is characterized by apparently normal development for the first 6 to 18 months of life, followed by regression of intellectual functioning, acquired fine and gross motor skills, and social skills. Purposeful use of the hands is replaced by repetitive stereotypical hand movements, such as hand-wringing.
Other clinical manifestations include seizures, disturbed breathing patterns with hyperventilation and periodic apnea, scoliosis, growth retardation, and gait apraxia.
There is wide variability in the rate of progression and severity of the disease. In addition to the typical (or classic) form of RTT, there are recognized atypical variants. Three distinct atypical variants have been described: preserved speech, early seizure, and congenital variants. RTT occurring in males is also considered a variant type and is associated with somatic mosaicism or Klinefelter (XXY) syndrome. A small number of RTT cases in males arising from the MECP2 exon 1 variant have been reported. Diagnostic criteria for typical (or classic) RTT and atypical (or variant) RTT have been established.
For typical RTT, a period of regression followed by recovery or stabilization and fulfillment of all the main criteria are required to meet the diagnostic criteria for classic RTT. For atypical RTT, a period of regression followed by recovery or stabilization, at least 2 of the 4 main criteria, plus 5 of 11 supportive are required to meet the diagnostic criteria of variant RTT.
Treatment
Currently, there are no specific treatments that halt or reverse disease progression, and there are no known medical interventions that will change the outcome of patients with RTT. Management is mainly symptomatic and individualized, focusing on optimizing each patient’s abilities.
A multidisciplinary approach is usually applied, with specialist input from dietitians, physical therapists, occupational therapists, speech therapists, and music therapists. Regular monitoring for scoliosis (seen in *87% of patients by age 25 years) and possible heart abnormalities, particularly cardiac conduction abnormalities, may be recommended. Spasticity
can have a major impact on mobility, and physical therapy and hydrotherapy may prolong mobility. Occupational therapy can help children develop communication strategies and skills needed for performing self-directed activities (eg, dressing, feeding, practicing arts and crafts).
Pharmacologic approaches to managing problems associated with RTT include melatonin for sleep disturbances and several agents to control breathing disturbances, seizures, and stereotypic movements. RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, and avoidance of a number of drugs is recommended, including prokinetic agents, antipsychotics, tricyclic antidepressants, antiarrhythmics, anesthetic agents, and certain antibiotics.
In a mouse model of RTT, genetic manipulation of the MECP2 gene has demonstrated reversibility of the genetic defect.
Genetics
RTT is an X-linked dominant genetic disorder. Pathogenic variants in the MECP2 gene, which is thought to control expression of several genes, including some involved in brain development, were first reported in 1999. Subsequent screening has shown that over 80% of patients with classic RTT have pathogenic variants in the MECP2 gene. More than 200 pathogenic variants in MECP2 have been associated with RTT.
However, 8 of the most commonly occurring missense and nonsense variants account for almost 70% of all cases, small C-terminal deletions account for approximately 10%, while large deletions are responsible for 8% to 10%.
MECP2 variant type is associated with disease severity.
Whole duplications of the MECP2 gene have been associated with severe X-linked intellectual disability with progressive spasticity, no or poor speech acquisition, and acquired microcephaly. Additionally, the pattern of X-chromosome inactivation influences the severity of the clinical disease in females.
Because the spectrum of clinical phenotypes is broad, to facilitate genotype-phenotype correlation analyses, the International Rett Syndrome Association has established a locusspecific MECP2 variation database (RettBASE) and a phenotype database (InterRett).
Approximately 99.5% of cases of RTT are sporadic, resulting from a de novo variant, which arises almost exclusively on the paternally derived X chromosome. The remaining 0.5% of cases are familial and usually explained by germline mosaicism or favorably skewed X-chromosome inactivation in a carrier mother that results in her being unaffected or only slightly affected (mild intellectual disability). In the case of a carrier mother, the recurrence risk of having RTT is 50%. If a variant is not identified in leukocytes of the mother, the risk to a sibling of the proband is below 0.5% (because germline mosaicism in either parent cannot be excluded).
Identification of a variant in MECP2 does not necessarily equate to a diagnosis of RTT. Rare cases of MECP2 variants have also been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked intellectual disability, PPMsyndrome (an X-linked genetic disorder characterized by psychotic disorders [most commonlbipolar disorder], parkinsonism, and intellectual disability), autism, and neonatal encephalopathy.
Recent studies have revealed that different classes of genetic variants inMECP2 result in variable clinical phenotypes and overlap with other neurodevelopmental disorders.
A proportion of patients with a clinical diagnosis of RTT do not appear to have pathogenic variants in the MECP2 gene. Two other genes (CDKL5, FOXG1) have been shown to be associated with atypical variants.
Wednesday, February 6, 2019
CPT 81479, 81599, 84999 -single nucleotide variant
Coding Code Description CPT
81479 Unlisted molecular pathology procedure
81599 Unlisted multianalyte assay with algorithmic analysis
84999 Unlisted chemistry procedure
Introduction
A “single nucleotide variant” (SNV) is a change in a specific section of a person’s DNA. These changes may increase a person’s risk of developing breast cancer. Medical studies have not shown that doing genetic tests to look at these SNVs is effective and reliable in predicting a person’s chance of getting breast cancer. For this reason, testing for one or more SNVs to predict a person’s risk of getting breast cancer is considered unproven (investigational).
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Testing Investigational
One or more single nucleotide variants (SNVs)
Testing for one or more single nucleotide variants (SNVs) to predict an individual’s risk of breast cancer is considered investigational.
BREVAGenplus® The BREVAGenplus® breast cancer risk test is considered investigational for all indications, including but not limited to use as a method of estimating an individual patient’s risk for developing breast cancer.
Note: BRCA genetic testing should be used in those from high-risk families (see Related Policies).
Related Information
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients. Genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Evidence Review
Description
A number of single nucleotide variants (SNVs), which are single base-pair variations in the DNA sequence of the genome, have been found to be associated with breast cancer and are common in the population but confer only small increases in the risk of getting breast cancer. Commercially available assays test for several SNVs to predict an individual’s risk of breast cancer relative to the general population. Some of these incorporate clinical information into risk prediction algorithms. The intent of this type of test is to identify subjects at increased risk who may benefit from more intensive surveillance.
Background
Gene Variants And Breast Cancer Risk
Rare, single-gene variants conferring a high risk of breast cancer have been linked to hereditary breast cancer syndromes. Examples are mutations in BRCA1 and BRCA2. These, and a few others, account for less than 25% of inherited breast cancer. Moderate risk alleles, such as variants in the CHEK2 gene, are also relatively rare and apparently explain very little of the genetic risk.
In contrast, several common SNVs associated with breast cancer have been identified primarily through genome-wide association studies (GWAS) of very large case-control populations. These alleles occur with high frequency in the general population, although the increased breast cancer risk associated with each is very small relative to the general population risk. Some have suggested that these common-risk SNVs could be combined for individualized risk prediction either alone or in combination with traditional predictors. Personalized breast cancer screening programs could then vary by the starting age and intensity of screening according to the person’s risk. Along these lines, the American Cancer Society recommends that women at high risk (>20% lifetime risk) should undergo breast magnetic resonance imaging (MRI) and a mammogram every year, and those at moderately increased risk (15%-20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram.
Clinical Genetic Tests
BREVAGenplus®
BREVAGenplus® (Phenogen Sciences, Charlotte, NC) evaluates breast cancer-associated SNVs identified in GWAS. The first-generation test, BREVAGen, included 7 SNVs. In a 2015 report, the test included over 70 susceptibility SNVs.
Risk is calculated by combining individual SNV risks with the Gail model risk. BREVAGenplus® has been evaluated for use in African-American, white, and Hispanic patient samples age 35 years and older. BREVAGenplus® does not detect known high-risk mutations (eg, in BRCA). According to the BREVAGenplus® website, the test is not applicable to women who are already at high risk of breast cancer including those that have a personal or extensive family history of breast and/or ovarian cancer, LCIS [lobular carcinoma in situ], DCIS [ductal carcinoma in situ], AH [atypical hyperplasia] or have had prior thoracic RT [radiotherapy] under age 30. Any women with these risk factors are already at increased risk of breast cancer and should be screened and followed as such.Genetic Testing for Rett Syndrome
81479 Unlisted molecular pathology procedure
81599 Unlisted multianalyte assay with algorithmic analysis
84999 Unlisted chemistry procedure
Introduction
A “single nucleotide variant” (SNV) is a change in a specific section of a person’s DNA. These changes may increase a person’s risk of developing breast cancer. Medical studies have not shown that doing genetic tests to look at these SNVs is effective and reliable in predicting a person’s chance of getting breast cancer. For this reason, testing for one or more SNVs to predict a person’s risk of getting breast cancer is considered unproven (investigational).
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Testing Investigational
One or more single nucleotide variants (SNVs)
Testing for one or more single nucleotide variants (SNVs) to predict an individual’s risk of breast cancer is considered investigational.
BREVAGenplus® The BREVAGenplus® breast cancer risk test is considered investigational for all indications, including but not limited to use as a method of estimating an individual patient’s risk for developing breast cancer.
Note: BRCA genetic testing should be used in those from high-risk families (see Related Policies).
Related Information
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients. Genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Evidence Review
Description
A number of single nucleotide variants (SNVs), which are single base-pair variations in the DNA sequence of the genome, have been found to be associated with breast cancer and are common in the population but confer only small increases in the risk of getting breast cancer. Commercially available assays test for several SNVs to predict an individual’s risk of breast cancer relative to the general population. Some of these incorporate clinical information into risk prediction algorithms. The intent of this type of test is to identify subjects at increased risk who may benefit from more intensive surveillance.
Background
Gene Variants And Breast Cancer Risk
Rare, single-gene variants conferring a high risk of breast cancer have been linked to hereditary breast cancer syndromes. Examples are mutations in BRCA1 and BRCA2. These, and a few others, account for less than 25% of inherited breast cancer. Moderate risk alleles, such as variants in the CHEK2 gene, are also relatively rare and apparently explain very little of the genetic risk.
In contrast, several common SNVs associated with breast cancer have been identified primarily through genome-wide association studies (GWAS) of very large case-control populations. These alleles occur with high frequency in the general population, although the increased breast cancer risk associated with each is very small relative to the general population risk. Some have suggested that these common-risk SNVs could be combined for individualized risk prediction either alone or in combination with traditional predictors. Personalized breast cancer screening programs could then vary by the starting age and intensity of screening according to the person’s risk. Along these lines, the American Cancer Society recommends that women at high risk (>20% lifetime risk) should undergo breast magnetic resonance imaging (MRI) and a mammogram every year, and those at moderately increased risk (15%-20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram.
Clinical Genetic Tests
BREVAGenplus®
BREVAGenplus® (Phenogen Sciences, Charlotte, NC) evaluates breast cancer-associated SNVs identified in GWAS. The first-generation test, BREVAGen, included 7 SNVs. In a 2015 report, the test included over 70 susceptibility SNVs.
Risk is calculated by combining individual SNV risks with the Gail model risk. BREVAGenplus® has been evaluated for use in African-American, white, and Hispanic patient samples age 35 years and older. BREVAGenplus® does not detect known high-risk mutations (eg, in BRCA). According to the BREVAGenplus® website, the test is not applicable to women who are already at high risk of breast cancer including those that have a personal or extensive family history of breast and/or ovarian cancer, LCIS [lobular carcinoma in situ], DCIS [ductal carcinoma in situ], AH [atypical hyperplasia] or have had prior thoracic RT [radiotherapy] under age 30. Any women with these risk factors are already at increased risk of breast cancer and should be screened and followed as such.Genetic Testing for Rett Syndrome
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