Medical Policy

 

Subject: Genetic Testing for Colorectal Cancer Susceptibility
Document #: GENE.00028 Publish Date:    03/29/2018
Status: Revised Last Review Date:    03/22/2018

Description/Scope

This document addresses genetic testing for individuals who are at higher than average risk for the development of colorectal cancer.  Genetic tests addressed in this document include, but are not limited to the following:

For additional information on genetic testing for malignant conditions, please refer to:

Note: Although immunohistochemistry (IHC) and microsatellite instability (MSI) are discussed in this document, this document is not meant to provide testing criteria for IHC or MSI.

Position Statement

Medically Necessary:

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC])

  1. Genetic testing for Lynch syndrome is considered medically necessary when information is available that may guide targeted testing, (that is: one of criteria A or B) and all of criteria C are met:
    1. IHC shows loss of nuclear staining for one or more of the mismatch repair enzymes and gene testing is guided by these results; or
    2. The individual has a family history of a known mutation in the MSH1, MSH2, MSH6, PMS2 or EPCAM genes; and
    3. Genetic counseling, which encompasses all of the following components, has been performed: 
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
  2. Genetic testing for Lynch syndrome is considered medically necessary when information that may guide targeted testing is unavailable, (that is: one of criteria A), and any one of criteria B through K and all of criteria L are met:
    1. Information that may guide targeted testing is unavailable:
      1. There are no IHC tumor testing results; or
      2. There is no family history of a known mutation in the MSH1, MSH2, MSH6, PMS2 or EPCAM genes; or
      3. The affected family member or proband is unavailable for testing; and
    2. Individual has a colorectal or endometrial cancer diagnosed prior to 50 years of age; or
    3. Individual with colorectal or endometrial cancer diagnosed at any age when there is a family history of a first-degree or second-degree relative with Lynch syndrome-related cancer§ diagnosed prior to 50 years of age; or
    4. Individual with colorectal or endometrial cancer diagnosed at any age when there is a family history of 2 or more first-degree or second-degree relatives with Lynch syndrome-related cancer§ diagnosed at any age; or
    5. The individual has a history of synchronous or metachronous Lynch syndrome-related tumor(s) §, regardless of age; or  
    6. The individual has a personal history of colorectal or endometrial cancer and the tumor shows evidence of mismatch repair deficiency (either high microsatellite instability [MSI] or loss of mismatch repair protein expression) at any age; or
    7. Individual has a predicted risk for Lynch syndrome greater than 5% on one of the following prediction models: MMRpro, PREMM or MMRpredict; or  
    8. The individual for whom the test is requested, has a first-degree relative with 2 or more Lynch syndrome-related tumors§, including synchronous and metachronous tumors; or
    9. The individual for whom the test is requested, has 2 or more first- or second-degree relatives with a history of a Lynch syndrome-related cancer§, including at least 1 relative which was diagnosed with a Lynch syndrome-related cancer§ prior to age 50; or
    10. The individual for whom the test is requested, has a first-degree relative with colorectal cancer or endometrial cancer diagnosed prior to age 50; or
    11. The individual for whom the test is requested, has a family history of 3 or more first-degree or second-degree relatives with Lynch syndrome-related cancers§, regardless of age; and
    12. Genetic counseling, which encompasses all of the following components, has been performed: 
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
        § Lynch-related tumors (cancers) include: colorectal, gastric, small bowel, endometrial, ovarian, pancreas, ureter, renal pelvis, biliary tract, brain, sebaceous gland adenomas and keratocanthomas.

Familial Adenomatous Polyposis (FAP) and Attenuated FAP (AFAP)

  1. Genetic testing to detect mutations in the APC (adenomatous polyposis coli) gene is considered medically necessary when any one of criteria A through D and all of criteria E are met:
    1. Individuals with greater than 10 adenomatous colonic polyps during their lifetime; or
    2. First- or second-degree relatives of individuals diagnosed with FAP or AFAP; or
    3. First- or second-degree relatives of individuals with a known APC gene mutation; or
    4. Individuals with a personal history of a desmoid tumor; and
    5. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.

MYH (Human MutY homolog)-associated Polyposis (MAP)

  1. Genetic testing for MYH (also known as MUTYH) -associated polyposis (MAP) is considered medically necessary when either criterion A or B and all of criteria C are met:
    1. The individual has greater than 10 adenomatous colonic polyps; or
    2. The individual is asymptomatic and has a first-degree relative with known MAP mutation; and
    3. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.

Investigational and Not Medically Necessary:

Genetic testing for colon or rectal cancer susceptibility is considered investigational and not medically necessary in individuals not meeting any of the criteria above.  

Genetic testing for colorectal cancer susceptibility using panels of genes (with or without next-generation sequencing), including, but not limited to ColoNext™, are considered investigational and not medically necessary unless all components of the panel have been determined to be medically necessary based on the criteria above.  However, individual components of a panel may be considered medically necessary when criteria above are met.

Note: When a component of a genetic panel is separately identified, but a specific medical necessity statement is not found above or in another document, the criteria in GENE.00001 Genetic Testing for Cancer Susceptibility may be used to determine medical necessity.

Rationale

Lynch Syndrome (Hereditary Non-Polyposis Colon Cancer [HNPCC])

Lynch syndrome is defined as a hereditary predisposition to colorectal cancer (CRC) and other malignancies including endometrial and gastric cancer.  Lynch syndrome is the most common form of genetically determined colon cancer and accounts for 3% of all newly diagnosed CRC cases and 3% of endometrial cancers.  This predisposition is a result of a mismatch repair (MMR) germ-line (constitutional) gene mutation (MLH1, MSH2, MSH6, and PMS2).  It has been estimated that approximately 80% of MMR mutations are located in the MLH1 and MSH2 genes, while approximately 10%–12% in the MSH6 gene and roughly 2%-3% in the PMS2 gene.  Pathogenic genetic alterations might be frameshift, nonsense and splice site mutations that result in truncating or unstable proteins.  Large deletions and rearrangements are also common.  Therefore, full germline genetic testing including both DNA sequencing and large rearrangement analysis has been recommended (Balmana, 2013).

Mutations in three additional genes (MLH3, PMS1, and EX01) have also been found to be associated with Lynch Syndrome.  MMR gene mutations are found in over half of the individuals meeting the clinical criteria for Lynch syndrome.  The lifetime risk of CRC is nearly 80% in individuals carrying a mutation in one of these genes. 

Identification of Individuals at Risk for Lynch Syndrome

A mutation in one of the four MMR genes (MLH1, MSH2, MSH6, and PMS2) results in the Lynch syndrome.  A definitive diagnosis can be made by gene sequencing.  Gene mutation testing for Lynch syndrome is directed by the individual’s personal and family history and, when available, preliminary screening tests for microsatellite instability and/or IHC on tumor tissue. 

There is also evidence that deletions in the epithelial cell adhesion molecule (EPCAM, also known as TACSTD1) gene are also a contributor to Lynch syndrome.  EPCAM is not an MMR gene, but can disrupt the MMR pathway.  EPCAM deletions result in inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.  Large deletions of the EPCAM gene can lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing.  It has been estimated that EPCAM deletions may account for 20-25% of cases in which MSH2 protein is not detected by IHC but germline MSH2 mutations are not identified.  In a table that describes testing strategies based on tumor screening results, the National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High Risk Assessment: Colorectal Cancer indicate that germline mutation testing of the EPCAM gene is appropriate when the tumor IHC stain is negative (absent) for both MSH2 and MSH6 and genetic testing for MSH2 is negative (Kempers, 2011; NCCNb, 2017; Rumilla, 2011).

The identification of Lynch syndrome is important for individuals with cancer because of the increased risk for metachronous Lynch syndrome cancers, and for their relatives because of autosomal dominant inheritance and potentially high penetrance.  Once Lynch syndrome has been identified, surveillance provides an opportunity for early detection and possibly the prevention of cancer among mutation carriers.  

Two phenotypic tests performed on colon cancer tissue to identify individuals at risk for Lynch Syndrome are used by themselves or together as initial screening tests.  These are used to screen individuals with colon cancer who have a clinical or family history suggesting Lynch Syndrome.  The most widely used is a test which measures “microsatellite instability” or MSI.  Microsatellites are repeated sequences of DNA which normally occur thousands of times across the genome.  These sequences are made of repeating units of 1-6 base pairs in length.  Each individual has microsatellites of a set length.  MSI resulting from impaired DNA MMR occurs in 80%-90% of Lynch syndrome CRC tumors.  MSI is a phenotypic expression of MMR gene mutations.  The function of the MMR gene is to correct errors which spontaneously occur during DNA replication.  The MMR gene products form a complex that binds to the mismatch, identifies the correct strand of DNA, then excises the error and repairs the mismatch.  Cells carrying an MMR mutation can accumulate microsatellite replication errors resulting in novel repeated DNA sequences (microsatellites) or microsatellite instability.  Five markers have been recommended by the National Cancer Institute to screen for MSI in HNPCC (Bethesda markers).  MSI detection in two of these markers is considered a positive result or “high probability of MSI” (Sinn, 2009). 

The second screening test for Lynch syndrome performed on colon cancer tissue involves IHC.  IHC involves staining of tumor tissue for protein expression of the four mismatch genes associated with Lynch Syndrome (MLH1, MSH2, MSH6, and PMS2).  If at least one of these four gene products is absent by IHC, the test is considered abnormal.  Both MSI and IHC have a 5-10% false negative rate and are often used as preliminary screening tests to select individuals for gene mutation testing.  MSI testing performance depends on the specific MMR mutation.  For MLH1or MSH2 mutations, MSI has a sensitivity of 80-91% and specificity of 90% while for MSH6 or PMS2 the sensitivity is lower (55-77%) and the specificity is 90%.  IHC testing, regardless of MMR gene mutation, has a sensitivity of 83% and specificity of 89% (EGAPP Working Group, 2009).

Several criteria sets have been developed over the years to identify individuals who should be tested for possible Lynch Syndrome.  The Amsterdam I criteria were proposed to identify individuals who were likely Lynch syndrome mutation carriers.  These criteria require the presence of early onset CRC in addition to a family history which includes 3 CRCs involving two successive generations.  The Amsterdam I criteria were later modified to include other Lynch syndrome-related malignancies.  Based on the Amsterdam II criteria, Lynch syndrome should be suspected in individuals with 3 or more relatives with an HNPCC-related cancer in addition to all of the following:

Although the Amsterdam II criteria are considered by many to be very stringent, it has been estimated that these criteria may miss as many as 68% individuals with Lynch syndrome.  It has also been estimated that approximately 50% of the families fulfilling the Amsterdam II criteria have an MMR gene mutation.

The National Cancer Institute developed the “Revised Bethesda Guidelines” in 2004 to identify colon cancer patients whose tumors should be tested for MSI.  These guidelines are now used to identify tumors that should be tested for mismatch repair defect, either by MSI and/or IHC.  These guidelines are more sensitive than another criteria set, “Revised Amsterdam Minimum Criteria for Clinical Definition of HNPCC” or Amsterdam Criteria II.  However, up to 50% of individuals with Lynch Syndrome fail to meet the revised Bethesda guidelines.  Hampel and colleagues (2008) found that limiting colon tumor analysis only to those individuals who fulfill Bethesda criteria would fail to identify 28% of cases of Lynch syndrome.  Some have advocated IHC and/or MSI screening of all CRCs and endometrial cancers regardless of age at diagnosis or family history.  This approach was endorsed for colon cancer by the EGAPP Working Group from the Center for Disease Control (EGAPP Working Group, 2009).  A survey of US hospitals reported that routine tumor testing with HHC, MSI or both is currently performed at 71% of NCI cancer centers, 36% of American College of Surgeons accredited community hospital cancer programs, but only 15% of community hospitals.  Given the small portion (2%-4%) of colorectal cancers associated with the Lynch Syndrome, there is varied opinion as to which colorectal tumors should be screened with MSI and/ or IHC (Hampel, 2008; NCCNb, 2017; Palomaki, 2009).

Prediction Models
Several validated computer models are available to estimate the likelihood that an individual affected with cancer carries a pathogenic variant in an MMR gene associated with Lynch syndrome. These include but are not limited to the MMRpro, MMRpredict, and PREMM1, 2, 6 (Prediction of Mismatch Repair Gene Mutations in MLH1, MSH2, and MSH6) prediction models.  While the general purpose of each model is the same, each has been developed differently. 

The NCCN recommends that testing for Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM sequence analysis) includes individuals who meet the Bethesda guidelines, the Amsterdam criteria, who have a cancer diagnosis prior to age 50, or have a predicted risk for Lynch syndrome greater than 5% on one of the following prediction models: MMRpredict, MMRpro or PREMM1, 2, 6 (NCCNb, 2017).

Surveillance in individuals with Lynch Syndrome has been shown to reduce the risk of CRC and may also lead to earlier diagnosis of endometrial cancer, also common in these individuals.  Other malignancies occur with increased frequency in Lynch Syndrome including gastric, ovarian, pancreas, urethra, glioblastoma, small intestine cancers, as well as sebaceous gland adenomas, and keratoacanthomas. 

Familial Adenomatous Polyposis (FAP) and Attenuated FAP

Classical FAP and attenuated FAP (AFAP) are autosomal dominant genetic disorders caused by a germline mutation in the APC (adenomatous polyposis coli) gene.  Nearly 80% of FAP individuals have a truncating mutation of the APC gene.  FAP accounts for less than 1% of all colorectal cancers, but individuals harboring APC gene mutations are recommended early enhanced screening, with colectomy or proctocolectomy when the polyp burden becomes heavy and cannot be effectively managed by polypectomy.  A clinical diagnosis of classical FAP is based on the presence of at least 100 polyps although fewer polyps may be present in younger age groups.  The lifetime risk for colon cancer (most are left sided) with classic FAP approaches 100% by the age 50.  At older ages, individuals with FAP may exhibit hundreds to thousands of colonic adenomatous polyps.  Individuals with FAP are also at a higher risk for developing other cancers, including duodenal cancer, hepatoblastoma and thyroid cancer.  Other possible associated findings of individuals with FAP include desmoid tumors, and congenital hypertrophy of retinal pigment epithelium.  Currently, family members are often diagnosed at adolescence with genetic testing for their specific familial mutation (NCCNb, 2017).

Attenuated FAP is a variant of FAP with a later onset of disease and fewer adenomatous polyps, usually 10 to less than 100.  Adenomatous polyps in AFAP are more likely to occur in the right colon and may take the form of diminutive sessile adenomatous polyps.  The onset of colon cancer is later with AFAP, but by age 80 the risk of colon cancer is nearly 70%.  Both FAP and AFAP have an increased risk of other cancers, including duodenal cancer, hepatoblastoma and thyroid cancer.  Individuals with FAP and AFAP are also at increased risk of developing desmoid tumors which are nonmalignant, but may become life threatening due to their locally invasive and aggressive growth.  Confirmation of FAP and AFAP requires the identification of a germline mutation in the APC gene (NCCNb, 2017).

MYH-associated Polyposis

MYH (also known as MUTYH)-associated polyposis (MAP) is an autosomal recessive inherited polyposis syndrome that predisposes some individuals to attenuated adenomatous polyposis and colorectal cancer.  Mutations in the MutY human homolog (MUYTH or MYH) gene prevent cells from correcting mistakes that are made when DNA is copied (DNA replication) in preparation for cell division.  The gene product is a DNA glycosylase which enables oxidative DNA damage repair.  The majority of individuals with MAP generally have fewer than 100 polyps although there are some instances where the individuals have greater than 1000 polyps.  Traditional serrated adenomas as well as hyperplastic polyps and sessile serrated polyps (SSP) may also be seen in this setting.  Some individuals with MAP may also meet the criteria for serrated polyposis syndrome (SPS).  The median age of affected individuals at the time of diagnosis is typically between the mid-40s and the late 50s.  Individuals with MAP develop fewer adenomas at a later age than individuals with APC mutations, but also carry a high risk of CRC (35-63%).  Studies of multiple FAP registries have shown that 7%-19% of individuals with the FAP phenotype but without detectable APC mutation carry biallelic mutations in the MYH gene (NCI, 2017).

Genetic testing for APC and/or MUTYH is important to distinguish between FAP/AFAP, MAP and colonic polyposis of unknown etiology.  Grover and colleagues (2012) conducted a cross-sectional study of more than 7000 individuals and found that the prevalence of pathogenic APC mutation was 80% for individuals with at least 1000 adenomas, 56% for individuals with 100-999 adenomas, 10% for individuals with 20-99 adenomas, and 5% for those with 10-19 adenomas.  In the same cohort, the prevalence of biallelic MUTYH mutations was 2%, 7%, 5% and 4%, respectively. 

Genetic Testing Using Panels of Genes

Until recently, genetic testing for cancer susceptibility was generally carried out by direct sequencing which analyzes a specific gene for a particular mutation.  However, next-generation sequencing, (including but not limited to massively parallel sequencing, and microarray testing) has made it possible to conduct panel testing which involves the analysis of multiple genes for multiple mutations simultaneously.  Panel testing has the potential benefit of analyzing multiple genes more rapidly and thereby providing the results of the genetic work-up in a more timely fashion.  However, the newer sequencing techniques may be associated with a higher error rate and lower diagnostic accuracy than direct sequencing which could affect the clinical validity of testing.  Another potential drawback of the newer technologies is that they may provide information on genetic mutations which is of uncertain clinical significance.  In assessing the value of a specific genetic testing panel for susceptibility to a particular malignant condition, consideration should be given to the peer-reviewed, published literature addressing the analytical validity, clinical validity, and clinical utility of the test.  Also, evidence demonstrating a positive impact of the panel on the care of individuals with, or at risk for, a specific cancer should be considered.

There is limited published evidence for the clinical utility and clinical validity of specific genetic test panels for colorectal cancer susceptibility.  While testing these genes may be appropriate in individuals with clinical or family histories suggestive of a specific syndrome, there is no evidence that mass screening of multiple genes in individuals suspected of having or being at risk for a hereditary CRC syndrome improves clinical outcomes.  Several genetic testing panels are currently available commercially.  The specific genes included in these test panels may differ between manufacturers.  At the present time, there is limited published information on their analytical validity, clinical utility or clinical validity.

Background/Overview

Lynch Syndrome (Hereditary Non-Polyposis Colon Cancer [HNPCC]), Familial Adenomatous Polyposis and MYH-associated Polyposis

Factors which suggest a genetic condition may be contributing to CRC include: (1) a strong family history of polyps and/or colorectal cancer; (2) multiple primary cancers in an individual with CRC; (3) the existence of other cancers within the kindred which are consistent with known syndromes associated with an inherited risk of CRC (for example, endometrial cancer); and (4) CRC diagnosed at an early age.  Hereditary CRC is most often inherited in an autosomal dominant pattern, although MUTYH-associated polyposis is inherited in an autosomal recessive manner (NCI, 2017).

There are multiple well-defined types of hereditary colorectal cancer; three of the most common are familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC) and MYH-associated Polyposis (MAP).  FAP can be clinically recognized by the presence of hundreds of colon polyps, typically apparent by age 10-20.  If left untreated, affected individuals will go on to develop colorectal cancer.  Individuals with HNPCC tend to have early-onset colorectal cancer, right-sided tumors and/or multiple synchronous or metachronous lesions.  Extracolonic tumors may also be present.  The lifetime risk of developing colorectal cancer in HPNCC is approximately 80%.  Germline mutations have been associated with both FAP and HNPCC creating the option of genetic testing of both affected individuals (to establish the genetic basis of the tumor) and their family members (to determine whether an individual carries the same mutation as the affected relative).  Subjects with germline mutations may undergo increased surveillance or may consider prophylactic colectomy.

Some mutations in the EPCAM gene are associated with Lynch syndrome.  The EPCAM gene lies next to the MSH2 gene and provides instructions for making an individual messenger RNA (mRNA), which serves as the genetic blueprint for making the protein.  EPCAM gene mutations cause the MSH2 gene to become inactivated by a mechanism known as promoter hypermethylation.  The MSH2 protein is crucial in repairing mistakes in DNA.  Loss of this protein prevents proper DNA repair and may result in uncontrolled cell growth and an increased risk of cancer. 

MAP is an autosomal recessive form of FAP that increases the individual’s risk of developing attenuated adenomatous polyposis and colorectal cancer.  There may also be an increased risk of polyps in the duodenum, although the incidence of duodenal polyposis is reported less frequently than in FAP.  The magnitude of the risk of duodenal cancer has not yet been defined.  As in the case of FAP, some individuals with MYH mutations may require colectomy, but the procedure is usually done at a later age than those with FAP.

Genetic Testing Using Panels of Genes

Next generation sequencing addresses any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.  Next generation sequencing is not a specific sequencing technology or a test in itself.  Instead, the term emphasizes the difference between the earlier testing methods that involved the sequencing of one DNA strand at a time.  Next generation sequencing includes but is not limited to massively parallel sequencing and microarray analysis. 

Next generation sequencing has led to the development of genetic testing incorporating panels which analyze multiple genes for multiple mutations simultaneously.  Researchers are investigating genetic testing using panels of genes as a means to identify genetic mutations that may contribute to the development of hereditary cancers.  Various laboratories have begun to offer next-generation sequencing panels.  The ColoNext™ test (manufactured by Ambry Genetics) is one such example, that tests for variants in 14 genes that have been associated with hereditary CRC, including the genes that cause Lynch syndrome (MLH1, MSH2, MSH6, PMS2 and EPCAM) as well as the gene that causes FAP (APC).

Genetic Counseling

According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease.  This process typically includes the guidance of a specially trained professional who:

  1. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
  2. Provides education about inheritance, genetic testing, disease management, prevention and resources; and
  3. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
  4. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006).
Definitions

Desmoid tumor: A type of benign, locally invasive fibrous tumor capable of growing anywhere in the body.

Familial adenomatous polyposis (FAP): An inherited disorder characterized by the presence of adenomatous polyps throughout the colon that commonly progress to develop colon cancer.

First-degree relative: Any relative who is a parent, sibling, or offspring to another.

Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Hereditary nonpolyposis colorectal cancer (HNPCC [Lynch Syndrome]): An inherited colorectal cancer syndrome that accounts for 5% to 8% of all colorectal cancers.

Hypermethylation: A process that occurs when additional methyl groups are added to the cytosine or adenine DNA nucleotides.

Medullary thyroid cancer: The type of thyroid cancer that develops from the C cells of the thyroid gland.

Multiple endocrine neoplasia Type 2 (MEN2): A hereditary disorder in which individuals develop a type of thyroid cancer accompanied by recurring cancer of the adrenal glands.

Mutation: A change in DNA sequence.

Next generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes. This technology includes but is not limited to massively parallel sequencing and microarray analysis.

Second-degree relative: Any relative who is a grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling to another.

Third-degree relative: Any relative who is a first cousin, great grandparent or great grandchild.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC])
When services may be Medically Necessary when criteria are met:

CPT

 

81288

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis

81292

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81293

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

81294

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81295

MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81296

MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

81297

MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81298

MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81299

MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

81300

MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81317

PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81318

PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

81319

PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons):

  • EPCAM (epithelial cell adhesion molecule) (eg, Lynch syndrome), duplication/deletion analysis

 

 

ICD-10 Diagnosis

 

 

C16.0-C16.9

Malignant neoplasm of stomach

 

C17.0-C17.9

Malignant neoplasm of small intestine

 

C18.0-C20

Malignant neoplasm of colon, rectosigmoid junction, rectum

 

C23

Malignant neoplasm of gallbladder

 

C24.0-C24.9

Malignant neoplasm of other and unspecified parts of biliary tract

 

C25.0-C25.9

Malignant neoplasm of pancreas

 

C54.0-C54.9

Malignant neoplasm of corpus uteri

 

C56.1-C57.9

Malignant neoplasm of ovary and other and unspecified female genital organs

 

C65.1-C66.9

Malignant neoplasm of renal pelvis, ureter

 

C71.0-C71.9

Malignant neoplasm of brain

 

D23.0-D23.9

Other benign neoplasms of skin [sebaceous glands]

 

L85.8

Other specified epidermal thickening [keratoacanthoma]

 

Z80.0

Family history of malignant neoplasm of digestive organs

 

Z80.41

Family history of malignant neoplasm of ovary

 

Z80.49

Family history of malignant neoplasm of other genital organs

 

Z80.51

Family history of malignant neoplasm of kidney

 

Z80.59

Family history of malignant neoplasm of other urinary tract organ

 

Z80.8

Family history of malignant neoplasm of other organs or systems

 

Z85.038

Personal history of other malignant neoplasm of large intestine

 

Z85.048

Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus

 

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When services are also Investigational and Not Medically Necessary:

CPT

 

81435

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11

81436

Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes including MLH1, MSH2, EPCAM, SMAD4, and STK11

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Familial Adenomatous Polyposis (FAP), Attenuated FAP (AFAP) and MYH (Human MutY homolog)-associated Polyposis (MAP)
When services may be Medically Necessary when criteria are met:

CPT

 

81201

APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence

81202

APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants

81203

APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants

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) [when specified as the following]:

  • MUTYH (mutY homolog [E.coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D)

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)  [when specified as the following]:

  • MUTYH (mutY homolog [E.coli]) (eg, MYH-associated polyposis), full gene sequence

 

 

ICD-10 Diagnosis

 

 

D12.0-D12.8

Benign neoplasm of colon, rectosigmoid junction, rectum

 

D37.4-D37.5

Neoplasm of uncertain behavior of colon, rectum [specified as colonic polyps]

 

D48.1

Neoplasm of uncertain behavior of connective and other soft tissue [desmoid tumor]

 

D49.0

Neoplasm of unspecified behavior of digestive system [specified as colonic polyps]

 

Z83.71

Family history of colonic polyps

 

Z86.010

Personal history of colonic polyps

 

Z87.39

Personal history of other diseases of the musculoskeletal system and connective tissue [desmoid tumor]

 

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Barnetson RA, Tenesa A, Farrington SM, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006; 354(26):2751-2763.
  2. Dinh TA, Rosner BI, Atwood JC, et al. Health benefits and cost-effectiveness of primary genetic screening for Lynch syndrome in the general population. Cancer Prev Res. 2011; 4(1):9-22.
  3. Goodfellow PJ, Billingsley CC, Lankes HA, et al. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: An NRG oncology and gynecologic oncology group study. J Clin Oncol. 2015; 33(36):4301-4308.
  4. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008; 26(35):5783-5788.
  5. Kastrinos F, Balmaña J, Syngal S. Prediction models in Lynch syndrome. Fam Cancer. 2013; 12(2): 217-228.
  6. Kastrinos F, Uno H, Ukaegbu C, et al. Development and validation of the PREMM5 model for comprehensive risk assessment of Lynch syndrome. J Clin Oncol. 2017; 35(19):2165-2172.
  7. Kattentidt Mouravieva AA, Geurts-Giele IR, de Krijger RR, et al. Identification of familial adenomatous polyposis carriers among children with desmoid tumours. Eur J Cancer. 2012; 48(12):1867-1874.
  8. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011; 12(1):49-55.
  9. Kuiper RP, Vissers LE, Venkatachalam R et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat 2011; 32(4):407-414.
  10. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009: 48(8):737-744.
  11. Palomaki GE, McClain MR, Melillo S et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009; 11(1):42-65.
  12. Ramsey SD, Clarke L, Etzioni R, et al. Cost-effectiveness of microsatellite instability screening as a method for detecting hereditary nonpolyposis colorectal cancer. Ann Intern Med. 2001; 135(8 Pt 1):577-588.
  13. Resnick KE, Hampel H, Fishel R, Cohn DE. Current and emerging trends in Lynch syndrome identification in women with endometrial cancer. Gynecol Oncol. 2009; 114(1):128-134.
  14. Resnick K, Straughn JM Jr, Backes F, et al. Lynch syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol. 2009; 114(3):530-536.
  15. Rumilla K, Schowalter KV, Lindor NM, et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011; 13(1):93-99.
  16. Sinn DH, Chang DK, Kim YH, et al. Effectiveness of each Bethesda marker in defining microsatellite instability when screening for Lynch syndrome. Hepatogastroenterology. 2009; 56(91-92):672-676.
  17. Smith LD, Tesoriero AA, Wong EM, et al. Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry. Breast Cancer Res. 2011; 13(1):R14.
  18. Strate LL, Syngal S. Hereditary colorectal cancer syndromes. Cancer Causes Control. 2005; 16(3):201-213.
  19. Vasen HF. Clinical diagnosis and management of hereditary colorectal cancer syndromes. J Clin Oncol. J Clin Oncol. 2000; 18(21 Suppl):81S-92S.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Board of Genetic Counselors. Genetic Counselors’ Scope of Practice. Available at: https://www.nsgc.org/p/cm/ld/fid=18#scope. Accessed on March 13, 2018.
  2. American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing. Gastroenterology. 2001; 121:195-197.
  3. Balmana J, Balaguer F, Cervantes A, et al. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2013; 24 Suppl 6:vi73-80.
  4. Evaluation of Genomic applications in Practice and Prevention. Working Group: Genetic testing strategies of newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.
  5. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2014; 80(2):197-220.
  6. Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101-116.
  7. National Cancer Institute. Genetics of Colorectal Cancer (PDQ) - Health Professional Version. Last updated February 15, 2018. Available at: https://www.cancer.gov/types/colorectal/hp/colorectal-genetics-pdq/. Accessed March 13, 2018.
  8. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology™. © 2017 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org. Accessed on March 12, 2018.
    • Colorectal Cancer Screening. V2.2017. Revised November 14, 2017.
    • Genetic/Familial High-Risk Assessment: Colorectal. V3.2017. Revised October 10, 2017.
  9. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
  10. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology position statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010; 28(5):893-901.
  11. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2):209-291.
  12. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004; 96(4):261-268.
  13. Vasen, HF, Watson P, Mecklin J P, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999; 116:1453-1456.
Websites for Additional Information
  1. National Cancer Institute. Division of Cancer Control & Population Sciences. Colorectal Cancer Risk Prediction Models. Updated February 1, 2018. Available at: https://epi.grants.cancer.gov/cancer_risk_prediction/colorectal.html. Accessed on March 13, 2018.
  2. National Library of Medicine (NLM). Genetics Home Reference. EPCAM. Reviewed May 2013. Published March 13, 2018. Available at: http://ghr.nlm.nih.gov/gene/EPCAM. Accessed on March 13, 2018.
Index

ColoNext
EPCAM
Attenuated Familial Adenomatous Polyposis (AFAP)
Familial Adenomatous Polyposis (FAP)
Genetic testing panels
Genetic testing using panels
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
Lynch Syndrome
MMRpredict
MMRpro
MYH-associated polyposis (MAP)
PREMM 1, 2, 6

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Revised

03/22/2018

Medical Policy & Technology Assessment Committee (MPTAC) review. Revised medically necessary criteria for Lynch syndrome to include “endometrial cancer” as appropriate. Moved the Amsterdam II and revised Bethesda criteria from the appendix section to the medically necessary section of the document. Removed the Appendix section. Added bullets “H” and “J”. Updated the Rationale, References, Index and History sections.

Revised

01/25/2018

MPTAC review.

Revised

01/17/2018

Hematology/Oncology Subcommittee review. Revised medically necessary criteria for Lynch syndrome. Added Appendix to the document. Updated the Rationale and Background/Overview and References sections of the document. The document header wording updated from “Current Effective Date” to “Publish Date.”

Revised

05/04/2017

MPTAC review.

Revised

05/03/2017

Hematology/Oncology Subcommittee review. Updated the medically necessary statements to include criteria for genetic counseling. Updated Background/Overview, Definitions, References and History sections. Updated formatting in the Position Statement section.

Reviewed

11/03/2016

MPTAC review.

Reviewed

11/02/2016

Hematology/Oncology Subcommittee review. Updated formatting in the Position Statement section. Updated Rationale, References and History sections.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Revised criteria for MYH (Human MutY homolog)-associated Polyposis (MAP). Updated review date, Rationale, References and History sections. Updated Coding section with 01/01/2016 CPT descriptor changes for 81435, 81436; removed ICD-9 codes.

Revised

11/13/2014

MPTAC review.

Revised

11/12/2014

Hematology/Oncology Subcommittee review. Expanded medically necessary criteria to address genetic testing for attenuated FAP (APC gene mutations). Updated review date, Description/Scope, Rationale, Definitions, References and History sections.  Updated Coding section to include 01/01/2015 CPT changes; removed CPT 81301 (not applicable).

New

11/14/2013

MPTAC review.

New

11/13/2013

Hematology/Oncology Subcommittee review. Initial document development. Clinical content relevant to colorectal cancer moved from GENE.00001 to this document. In the medically necessary section for HNPCC, added the following: (1) Criterion indicating genetic testing is medically necessary when an individual has personal history of colorectal or endometrial cancer and tumor shows high micro-satellite instability (MSI); and (2) Statement indicating genetic testing for EPCAM mutations is considered medically necessary to make a diagnosis of Lynch syndrome when criteria are met. Updated Coding section with 01/01/2014 HCPCS changes; removed S3833, S3834 deleted 12/31/2013.