Coverage Policy Manual
Policy #: 2004038
Category: Laboratory
Initiated: August 2004
Last Review: October 2018
  Genetic Test: Lynch Syndrome and Inherited Intestinal Polyposis Syndromes

Description:
Genetic testing is available for both affected individuals, as well as those at risk, for various types of hereditary cancer. This policy describes genetic testing for familial adenomatous polyposis (FAP), Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer or HNPCC), MYH-associated polyposis, and Lynch syndrome-related endometrial cancer.
 
There are currently 2 well-defined types of hereditary colorectal cancer, familial adenomatous polyposis (FAP) and Lynch syndrome (formerly hereditary nonpolyposis colorectal cancer or HNPCC). Lynch syndrome has been implicated in some endometrial cancers as well.
 
Familial adenomatous polyposis and associated variants
FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will go on to develop colorectal cancer. The mean age of colon cancer diagnosis in untreated individuals is 39 years. FAP accounts for about 1% of colorectal cancer and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina referred to as congenital hypertrophy of the retinal pigment epithelium (CHRPE). FAP associated with these collective extraintestinal manifestations is sometimes referred to as Gardner syndrome. FAP may also be associated with central nervous system (CNS) tumors, referred to as Turcot syndrome.
 
Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Mutations in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene mutation (I1307K) has been found in subjects of Ashkenazi Jewish descent that may explain a portion of the familial colorectal cancer occurring in this population.
 
A subset of FAP patients may have attenuated FAP (AFAP), typically characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP, colorectal cancer occurring at an average age of 50-55 years, but a high lifetime risk of colorectal cancer of about 70% by age 80 years. The risk of extra-intestinal cancer is lower compared to classical FAP but still high at an estimated cumulative lifetime risk of 38% compared to the general population (Vogt, 2009). Only 30% or fewer of AFAP patients have APC mutations; some of these patients instead have mutations in the MUTYH (formerly MYH) gene and are then diagnosed with MUTYH-associated polyposis (MAP). MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent. Biallelic MUTYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas monoallelic MUTYH mutation-associated risk of colorectal cancer appears to be relatively minimal, although still under debate (Balmana, 2010). Thus, inheritance for high-risk colorectal cancer predisposition is autosomal recessive in contrast to FAP. When relatively few (i.e., between 10 and 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MUTYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.
 
It is important to distinguish among classical FAP, attenuated FAP, and MAP (mono- or biallelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary according to the syndrome (Gala, 2011).
 
Genetic testing for APC mutations may be considered for the following types of patients:
 
    • Family members of patients with FAP and a known APC mutation. Those without the specific mutation have not inherited the susceptibility gene and can forego intense surveillance (although they retain the same risk as the general population and should continue an appropriate level of surveillance).
 
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. These patients do not meet the clinical diagnostic criteria for classical FAP and have few adenomatous colonic polyps.
 
    • Patients with colon cancer with a clinical picture or family history consistent with classical FAP.
 
Lynch Syndrome
Patients with Lynch syndrome have a predisposition to colorectal cancer and other malignancies as a result of an inherited mutation in a DNA mismatch repair (MMR) gene. Lynch syndrome includes those with an existing cancer and those who have not yet developed cancer. The term “HNPCC” originated prior to the discovery of explanatory MMR mutations for many of these patients and now includes some who are negative for MMR mutations and likely have mutations in as-yet unidentified genes. For purposes of clarity and analysis, the use of Lynch syndrome in place of HNPCC has been recommended in several recent editorials and publications.
 
Lynch syndrome is estimated to account for 3% to 5% of all colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer. Lynch syndrome is associated with a risk of developing colorectal cancer by age 70 years of approximately 27% to 45% for men, and 22% to 38% for women, after correction for ascertainment bias (Bonadona, 2011). Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years.  
 
Lynch syndrome is associated with any of a large number of possible mutations in 1 of several MMR genes, known as MLH1, MSH2, MSH6, PMS2 and rarely MLH3. Risk of all Lynch syndrome-related cancers is markedly lower for carriers of a mutation in the MSH6 and PMS2 genes, although for most cancers still significantly higher than that of the general population. (Gala, 2011; Bonadona 2011), Estimated cumulative risks of any associated cancer for a carrier of a mutation in any MMR gene do not begin to increase until after age 30 years.
 
Lynch syndrome mutations are heterozygous; that is, only one of the 2 gene alleles contains a mutation. In rare cases both alleles contain the mutation, i.e., biallelic MMR gene mutations. This unusual syndrome has been described in multiple families and is to a large extent the result of consanguinity (Durno, 2010). Children with biallelic MMR mutations may develop extra-colonic cancers in childhood, such as brain tumors, leukemias, or lymphomas. Those unaffected or surviving early malignancies are at high risk of later colorectal cancer (average age of colorectal cancer diagnosis 16.4 years) (Durno, 2010. Family history may not suggest Lynch syndrome. Prior to cancer diagnosis, patients may have multiple adenomatous polyps and thus may have an initial differential diagnosis of attenuated FAP versus MUTYH-associated polyposis versus Lynch syndrome.
 
About 70% of Lynch syndrome patients have mutations in either MLH1 or MSH2. Testing for MMR gene mutations is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2 testing. Large gene sizes and the difficulty of detecting mutations in these genes make direct sequencing a time- and cost-consuming process. Thus, additional indirect screening methods are needed to determine which patients should proceed to direct sequencing for MMR gene mutations. Available screening methods are microsatellite instability (MSI) testing or immunohistochemical (IHC) testing. BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency. A methylation analysis of the MLH1 gene can largely substitute for BRAF testing, or be used in combination to slightly improve efficiency.
 
Mutations in MMR genes result in a failure of the mismatch repair system to repair errors that occur during the replication of DNA in tumor tissue. Such errors are characterized by the accumulation of alterations in the length of simple, repetitive microsatellite (2 to 5 base repeats) sequences that are distributed throughout the genome, termed microsatellite instability (MSI) and resulting in a MSI-high tumor phenotype. MSI testing was standardized subsequent to a 2004 National Cancer Institute (NCI) workshop (Umar, 2004). Methodologic studies have also shown the importance of laser microdissection of the tumor tissue, comparison of tumor and normal cells, and a minimum proportion of tumor in relation to the quality of the test results. While the sensitivity of MSI testing is high, the specificity is low because approximately 10% of sporadic colorectal carcinoma (CRC) are MSI-positive due to somatic hypermethylation of the MLH1 promoter. Additionally, some tumors positive for MSH6 mutations are associated with the MSI-low phenotype rather than MSI-high; thus MSI-low should not be a criterion against proceeding to MMR mutation testing (Wu, 1999; Goel, 2010).
  
Absent or reduced protein expression may be a consequence of an MMR gene mutation. IHC assays for the expression of MLH1, MSH2, MSH6, and PMS2 can be used to detect loss of expression of these genes and to focus sequencing efforts on a single gene. It is also possible for IHC assays to show loss of expression, and thus indicate the presence of a mutation, when sequencing is negative for a mutation. In such cases, mutations may be in unknown regulatory elements and cannot be detected by sequencing of the protein coding regions. Thus IHC may add additional information.
 
The BRAF gene is often mutated in colorectal cancer; when a particular BRAF mutation (V600E, a change from valine to glutamic acid at amino acid position 600 in the BRAF protein) is present, to date no MLH1 gene mutations have been reported (Palomaki, 2009). Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 mutation, could first be screened for a BRAF mutation. BRAF-positive samples need not be further tested by MLH1 sequencing. MLH1 gene methylation largely correlates with the presence of BRAF-V600E and in combination with BRAF testing can accurately separate Lynch from sporadic colorectal cancer in IHC MLH1-negative cases (Bouzourene, 2010).
 
Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR mutations, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria (low sensitivity but high specificity) and the Bethesda guidelines (better sensitivity but poorer specificity). While family history is an important risk factor and should not be discounted in counseling families, it has poor sensitivity and specificity for identifying Lynch syndrome. Based on this and other evidence, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommended testing all newly diagnosed patients with colorectal cancer for Lynch syndrome, using a screening strategy based on MSI or IHC (+ BRAF) followed by sequencing in screen-positive patients. This recommendation includes genetic testing for the following types of patients:
    • Family members of Lynch syndrome patients with a known MMR mutation; family members would be tested only for the family mutation; those testing positive would benefit from early and increased surveillance to prevent future colorectal cancer.
    • Patients with a differential diagnosis of Lynch syndrome vs. attenuated FAP vs. MYH-associated polyposis [MAP].
    • Lynch syndrome patients. Genetic testing of the proband with colorectal cancer likely benefits the proband where Lynch syndrome is identified and appropriate surveillance for associated malignancies can be initiated and maintained and benefits family members by identifying the family mutation.
 
Recently, novel deletions have been reported to affect the expression of the MSH2 MMR gene in the absence of a MSH2 gene mutation, and thereby cause Lynch syndrome. In these cases, deletions in EPCAM, the gene for the epithelial cell adhesion molecule, are responsible. EPCAM testing has been added to many Lynch syndrome profiles and is conducted only when tumor tissue screening results are MSI-high, and/or IHC shows a lack of MSH2 expression, but no MSH2 mutation is found by sequencing.
 
Separately from patients with EPCAM deletions, rare Lynch syndrome patients have been reported without detectable germline MMR mutations although IHC testing demonstrates a loss of expression of one of the MMR proteins. In at least some of these cases, research has identified germline "epimutations," i.e., methylation of promoter regions that control the expression of the MMR genes (Hesson, 2010; Hitchins, 2010; Niessen, 2009). Such methylation may be isolated or in conjunction with a linked genetic alteration near the affected MMR gene. The germline epimutations may arise de novo or may be heritable in either Mendelian or non-Mendelian fashion. This is distinct from some cases of MSI-high sporadic colorectal cancer wherein the tumor tissue may show MLH1 promoter methylation and IHC non-expression, but the same is not true of germline cells. Clinical testing for Lynch syndrome-related germline epimutations is not routine but may be helpful in exceptional cases. Epimutations as a cause of Lynch syndrome are described only for informational purposes; no policy statement is made regarding this testing.
 
Female patients with Lynch syndrome have a predisposition to endometrial cancer. Lynch syndrome is estimated to account for 2% of all endometrial cancers in women and 10% of endometrial cancers in women younger than 50 years of age. Female carriers of the germline mutations MLH1, MSH2, MSH6, and PMS2 have an estimated 40-62% lifetime risk of developing endometrial cancer, as well as a 4-12% lifetime risk of ovarian cancer.
 
Juvenile Polyposis Syndrome
Juvenile polyposis syndrome (JPS) is an autosomal dominant genetic disorder characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract. It is rare, with an estimated incidence of 1 in 100,000 to 160,000. Generalized juvenile polyposis refers to polyps in the upper and lower gastrointestinal tract, and juvenile polyposis coli refers to polyps of the colon and rectum. Those with JPS are at a higher risk for colorectal and gastric cancer (Latchford, 2012). Approximately 60% of patients with JPS have a germline variant in the BMPR1A gene or the SMAD4 gene (Howe, 1998; Fogt, 2004). Approximately 25% of patients have de novo variants (Burger, 2002; Syngal, 2015). In most cases, polyps appear in the first decade of life and most patients are symptomatic by age 20 years (Grotsky, 1982). Rectal bleeding is the most common presenting symptom, occurring in more than half of patients. Other presenting symptoms include prolapsing polyp, melena, pain, iron deficiency anemia, and diarrhea (Latchford, 2012; Syngal, 2015; Grotsky, 1982).
 
As noted, individuals with JPS are at increased risk for colorectal and gastric cancer. By 35 years of age, the cumulative risk of CRC is 17% to 22%, which increases to 68% by age 60 years (Schrelbman, 2005; Brosens, 2007). The estimated lifetime risk of gastric cancer is 20% to 30%, with a mean age at diagnosis of 58 years (Latchford, 2012; Syngal, 2015; Schrelbman, 2005). JPS may also be associated with hereditary hemorrhagic telangiectasia (Gallione, 2004). The most common clinical manifestations of hereditary hemorrhagic telangiectasia are telangiectasias of the skin and buccal mucosa, epistaxis, and iron deficiency anemia from bleeding.
 
Diagnosis
A clinical diagnosis of JPS is made on the basis of the presence of any one of the following: at least 3 to 5 juvenile polyps in the colon or multiple juvenile polyps in other parts of the gastrointestinal tract or any number of juvenile polyps in a person with a known family history of juvenile polyps (NCCN, 2018). It is recommended that individuals who meet clinical criteria for JPS undergo genetic testing for a germline variant in the BMPR1A and SMAD4 genes for a confirmatory diagnosis of JPS and to counsel at-risk family members.
 
Peutz-Jeghers Syndrome
Peutz-Jeghers syndrome (PJS) is also an autosomal dominant genetic disorder, similar to JPS, and characterized by the presence of multiple hamartomatous (benign) polyps in the digestive tract, mucocutaneous pigmentation, and an increased risk of gastrointestinal and nongastrointestinal cancers. It is rare, with an estimated incidence of 1 in 8000 to 200,000. In most cases, a germline variant in the STK11 (LKB1) gene is responsible for PJS, which has a high penetrance of over 90% by the age of 30 years (Olschwang, 1998; Jenne, 1998; Hemminki, 1998). However, 10% to 20% of individuals with PJS have no family history and are presumed to have PJS due to de novo variants (Hernan, 2004). A variant in STK11 is detected in only 50% to 80% of families with PJS, suggesting that there is a second PJS gene locus.
 
The reported lifetime risk for any cancer is between 37% and 93% among those diagnosed with PJS with an average age of cancer diagnosis at 42 years. The most common sites for malignancy are colon and rectum, followed by breast, stomach, small bowel, and pancreas (van Lier, 2010). The estimated lifetime risk of gastrointestinal cancer ranges from 38% to 66%. 36 Lifetime cancer risk stratified by organ site is colon and rectum (39%), stomach (29%), small bowel (13%), and pancreas (11%-36%).
 
Diagnosis
A clinical diagnosis of PJS is made if an individual meets two or more of the following criteria: presence two or more histologically confirmed PJ polyps of the small intestine or characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, fingers, or family history of PJS (NCCN, 2018). Individuals who meet clinical criteria for PJS should undergo genetic testing for a germline variant in the STK11 gene for a confirmatory diagnosis of PJS and counseling at-risk family members. In addition, if there is a known SMAD4 variant in the family, genetic testing should be performed within the first 6 months of life due to hereditary hemorrhagic telangiectasia risk (NCCN, 2018).
 
Coding
 
Effective in 2015, there is a specific code for MLH1:
81288  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
  
Effective in 2013, there are specific CPT codes for genetic testing of APC:
81201-81203 APC genetic testing code range
Effective in 2015, there is a specific code for MLH1:
81288  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
 
Effective in 2012, there are specific CPT codes for genetic testing of MLH1, MSH2, MSH6, PMS2 and microsatellite instability:
81292-81294 MLH1 genetic testing code range
81295-81297 MSH2 genetic testing code range
81298-81300 MSH6 genetic testing code range
81301 Microsatellite instability analysis (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (e.g., BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
81317-81319 PMS2 genetic testing code range
 
Prior to 2012, there were no specific CPT codes for genetic testing; testing was typically coded for using a series of CPT codes describing the individual steps in the testing process. Prior to the establishment of the specific codes listed above, the following codes would have been reported:
   
Genetic Testing in Patients at Risk for Lynch Syndrome:
83890: Molecular diagnostics: molecular isolation or extraction; each nucleic acid type (i.e., DNA or RNA)
83894: Molecular diagnostics: separation by gel electrophoresis (e.g., agarose, polyacrylamide), each nucleic acid preparation
83898: Molecular diagnostics: amplification, target, each nucleic acid sequence
83902: Molecular diagnostics: reverse transcription
83912: Molecular diagnostics: interpretation and report
 
Genetic Testing in Patients at Risk for FAP
83890: Molecular diagnostics: molecular isolation or extraction; each nucleic acid type (i.e., DNA or RNA)
83892: Molecular diagnostics: enzymatic digestion; each enzyme treatment
83894: Molecular diagnostics: separation by gel electrophoresis (e.g., agarose, polyacrylamide), each nucleic acid preparation
83898: Molecular diagnostics: amplification, target, each nucleic acid sequence
83902: Molecular diagnostics: reverse transcription
83912: Molecular diagnostics: interpretation and report
 
There are CPT genetic testing modifiers specific to MLH1 (-0J), and MSH2, MSH6 or PMS2 (-0K).
 
Note: There are a series of HCPCS codes ( S3828, S3829, S3830, S3831)  that specifically describe genetic sequencing for MLH1 and MSH2, individually or together, or genetic testing for a single mutation in a known affected family as well as S3833 and S3834 that describe APC gene sequencing for susceptibility to familial adenomatous polyposis.. Therefore, these codes could be used in lieu of using CPT coding for the individual components of genetic testing.
 
Specific Testing Information
It is recommended that, when possible, initial genetic testing for FAP or Lynch syndrome be performed in an affected family member so that testing in unaffected family members can focus on the mutation found in the affected family member.  
 
In many cases, genetic testing for MUTYH gene mutations should first target the specific mutations Y165C and G382D, which account for more than 80% of mutations in Caucasian populations, and subsequently proceed to sequencing only as necessary. In other ethnic populations, however, proceeding directly to sequencing is appropriate.
 
For patients with colorectal cancer being evaluated for Lynch syndrome, either the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test with or without BRAF gene mutation testing,  should be used as an initial evaluation of tumor tissue prior to MMR gene analysis. Both tests are not necessary. Consideration of proceeding to MMR gene sequencing would depend on results of MSI or IHC testing. IHC testing in particular may help direct which MMR gene likely contains a mutation, if any, and may also provide some additional information if MMR genetic testing is inconclusive.
 
When indicated, genetic sequencing for MMR gene mutations should begin with MLH1 and MSH2 genes unless otherwise directed by the results of IHC testing. Standard sequencing methods will not detect large deletions or duplications; when MMR gene mutations are expected based on IHC or MSI studies but none are found by standard sequencing, additional testing for large deletions or duplications is appropriate.  
 
Several Clinical Laboratory Improvement Amendments (CLIA)-licensed clinical laboratories offer MMR gene mutation testing for Lynch syndrome. For example, the GeneTests website, available online at: (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2622?db=genetests) lists 17 U.S.-located laboratories that offer this service. In at least one laboratory, Lynch syndrome mutation testing is packaged under one copyrighted name. The COLARIS® test from Myriad Genetic Laboratories includes sequence analysis of MLH1, MSH2, MSH6 and PMS2; large rearrangement analysis for MLH1 MSH2, PMS2, and MSH6 large deletions/duplications; and analysis for large deletions in the EPCAM gene near MSH2. Note that there may be 2 versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing). Testing is likely done in stages, beginning with the most common types of mutations. Individualized testing (e.g., targeted testing for a family mutation) can also be requested.   
 
Similarly, GeneTests lists 15 U.S.-based CLIA-licensed clinical laboratories that provide APC mutation testing and 14 that provide MUTYH mutation testing. The COLARIS® AP test from Myriad Genetic Laboratories includes DNA sequencing analysis of the APC and MUTYH genes, as well as analysis of large rearrangements in the APC gene that are not detected by DNA sequencing.
  
 

Policy/
Coverage:
Effective October 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for APC gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
        • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with FAP and/or a known APC mutation.  
        • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.  
 
Genetic testing for MUTYH gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
        • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MUTYH-associated polyposis (autosomal recessive).  
 
Genetic testing for MMR gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
        • Patients with colorectal cancer, for the diagnosis of Lynch syndrome.  
        • Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer, for the diagnosis of Lynch syndrome.  
        • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known MMR mutation.  
        • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.  
        • Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations.  
 
Genetic testing for EPCAM mutations meets primary coverage criteria that there be scientific evidence of effectiveness when any one of the following 3 major criteria (solid bullets) is met:
        • Patients with colorectal cancer, for the diagnosis of Lynch syndrome when:  
            • Tumor tissue shows lack of MSH2 expression by immunohistochemistry and patient is negative for a germline mutation in MSH2; or   
            • Tumor tissue shows a high level of microsatellite instability and patient is negative for a germline mutation in MSH2, MLH1, PMS2, and MSH6; OR  
        • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known EPCAM mutation; OR  
        • Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria (see below), when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.  
 
Genetic testing for BRAF V600E or MLH1 promoter methylation meets primary coverage criteria that there be scientific evidence of effectiveness to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis.
 
Genetic testing for SMAD4 and BMPR1A gene variants meets primary coverage criteria that there be scientific evidence of effectiveness when any one of the following major criteria (solid bullets) is met:
        • Patients with a clinical diagnosis of juvenile polyposis syndrome based on the presence of any one of the following:
          • at least 3 to 5 juvenile polyps in the colon
          • multiple juvenile polyps in other parts of the gastrointestinal tract
          • any number of juvenile polyps in a person with a known family history of juvenile polyps.
        • At-risk relative of a patient diagnosed with juvenile polyposis syndrome.
 
Genetic testing for STK11 gene variants meets primary coverage criteria that there be scientific evidence of effectiveness when any one of the following major criteria (solid bullets) is met:
        • Patients with a clinical diagnosis of Peutz-Jeghers syndrome based on the presence of any 2 of the following:
          • presence of 2 or more histologically confirmed Peutz-Jeghers polyps of the small intestine
          • characteristic mucocutaneous pigmentation of the mouth, lips, nose, eyes, genitalia, or fingers
          • family history of Peutz-Jeghers syndrome
        • At-risk relative of a patient diagnosed with Peutz-Jeghers syndrome.
 
Pre- and post-test genetic counseling meets primary coverage criteria that there be scientific evidence of effectiveness as an adjunct to the genetic testing itself.
 
Amsterdam II Criteria (must meet all of the following):
        • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND  
        • HNPCC-associated cancer involving at least 2 generations; AND  
        • cancer in 1 or more affected relatives diagnosed before 50 years of age; AND  
        • familial adenomatous polyposis excluded in any cases of colorectal cancer.  
 
Revised Bethesda Criteria (may meet any of the following):
        • Individuals diagnosed with colorectal cancer before age 50; OR  
        • Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR  
        • Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR  
        • Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age <50 years; OR  
        • Individuals with colorectal cancer and colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors regardless of age.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational or Not Medically Necessary For Contracts Without Primary Coverage Criteria
 
Genetic testing for APC gene mutations to confirm a diagnosis of colorectal cancer patients with classical Familial Adenomatous Polyposis (FAP) does not meet primary coverage criteria because this testing is not cost effective since the diagnosis of classical FAP is based on clinical presentation. For members with contracts without primary coverage criteria, genetic testing for APC gene mutations for colorectal cancer patients with classical Familial Adenomatous Polyposis is considered investigational.  Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer is considered investigational. Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Effective December 2013 - September 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for APC gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
 
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with FAP and/or a known APC mutation.
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
 
Genetic testing for MUTYH gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MUTYH-associated polyposis (autosomal recessive).
 
Genetic testing for MMR gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
    • Patients with colorectal cancer, for the diagnosis of Lynch syndrome.
    • Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer, for the diagnosis of Lynch syndrome.
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known MMR mutation.
    •  Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
    • Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations.
 
Genetic testing for EPCAM mutations meets primary coverage criteria that there be scientific evidence of effectiveness when any one of the following 3 major criteria (solid bullets) is met:
    • Patients with colorectal cancer, for the diagnosis of Lynch syndrome when:
        • Tumor tissue shows lack of MSH2 expression by immunohistochemistry and patient is negative for a germline mutation in MSH2; or  
        • Tumor tissue shows a high level of microsatellite instability and patient is negative for a germline mutation in MSH2, MLH1, PMS2, and MSH6; OR
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known EPCAM mutation; OR
    • Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria (see below), when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.
 
Genetic testing for BRAF V600E or MLH1 promoter methylation meets primary coverage criteria that there be scientific evidence of effectiveness to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis.
 
 
Pre- and post-test genetic counseling meets primary coverage criteria that there be scientific evidence of effectiveness as an adjunct to the genetic testing itself.
 
Amsterdam II Criteria (must meet all of the following):
 
    • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND  
    • HNPCC-associated cancer involving at least 2 generations; AND  
    • cancer in 1 or more affected relatives diagnosed before 50 years of age; AND  
    • familial adenomatous polyposis excluded in any cases of colorectal cancer.  
 
Revised Bethesda Criteria (may meet any of the following):
    • Individuals diagnosed with colorectal cancer before age 50; OR  
    • Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR  
    • Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR  
    • Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age <50 years; OR  
    • Individuals with colorectal cancer and colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors regardless of age.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational or Not Medically Necessary For Contracts Without Primary Coverage Criteria
 
Genetic testing for APC gene mutations to confirm a diagnosis of colorectal cancer patients with classical Familial Adenomatous Polyposis (FAP) does not meet primary coverage criteria because this testing is not cost effective since the diagnosis of classical FAP is based on clinical presentation. For members with contracts without primary coverage criteria, genetic testing for APC gene mutations for colorectal cancer patients with classical Familial Adenomatous Polyposis is considered investigational.  Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, genetic testing for all other gene mutations for Lynch syndrome or colorectal cancer is considered investigational. Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Effective November 2012 – November 2013
Genetic testing for APC gene mutations meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
 
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with FAP and/or a known APC mutation.
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
 
Genetic testing for APC gene mutations to confirm a diagnosis of colorectal cancer patients with classical Familial Adenomatous Polyposis (FAP) does not meet primary coverage criteria because this testing is not cost effective since the diagnosis of classical FAP is based on clinical presentation. For contracts without primary coverage criteria, genetic testing for APC gene mutations for colorectal cancer patients with classical Familial Adenomatous Polyposis is considered investigational.  Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for MUTYH gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
 
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MYH-associated polyposis (autosomal recessive).
 
Genetic testing for MMR gene mutations meets primary coverage criteria in the following patients:
 
    • Patients with colorectal cancer, for the diagnosis of Lynch syndrome.
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known MMR mutation.
    • Patients with a differential diagnosis of attenuated FAP vs. MUTYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
    • Patients without colorectal cancer but with a family history meeting the Amsterdam (criteria detailed below) or Revised Bethesda criteria (criteria detailed below), when no affected family members have been tested for MMR mutations.
    • Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer, for the diagnosis of Lynch syndrome.
 
Genetic testing for EPCAM mutations may be considered medically necessary when any one of the following 3 major criteria (solid bullets) are met:
      • Patients with colorectal cancer, for the diagnosis of Lynch syndrome when:
          • Tumor tissue shows lack of MSH2 expression by immunohistochemistry and patient is negative for a germline mutation in MSH2; or  
          • Tumor tissue shows a high level of microsatellite instability and patient is negative for a germline mutation in MSH2, MLH1, PMS2, and MSH6; OR
      • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included)  of patients with Lynch syndrome with a known EPCAM mutation; OR
      • Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.
 
Pre- and post-test genetic counseling meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes as an adjunct to the genetic testing itself.
 
Amsterdam II Criteria (must meet all of the following):
        • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND
        • HNPCC-associated cancer involving at least 2 generations; AND
        • cancer in 1 or more affected relatives diagnosed before 50 years of age; AND
        • familial adenomatous polyposis excluded in any cases of colorectal cancer.
 
Revised Bethesda Criteria (may meet any of the following):
        • Individuals diagnosed with colorectal cancer before age 50; OR
        • Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR
        • Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR
        • Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age <50 years; OR
        • Individuals with colorectal cancer and colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors regardless of age.
 
Effective October 2010 through October 2012
Genetic testing for APC gene mutations meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
 
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with FAP and/or a known APC mutation.
    • Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
 
Genetic testing for APC gene mutations for colorectal cancer patients with classical Familial Adenomatous Polyposis does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  For contracts without primary coverage criteria, genetic testing for APC gene mutations for colorectal cancer patients with classical Familial Adenomatous Polyposis is considered investigational.  Investigational services are considered contract exclusions in most member benefit certificates of coverage.
 
Genetic testing for MYH gene mutations meets primary coverage criteria that there be scientific evidence of effectiveness in the following patients:
 
    • Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MYH-associated polyposis (autosomal recessive).
 
Genetic testing for MMR gene mutations meets primary coverage criteria in the following patients:
 
    • Patients with colorectal cancer, for the diagnosis of Lynch syndrome.
    • At-risk relatives (primarily first-degree relatives, however some judgment must be allowed for example, in the case of a small family pedigree, extended family members may need to be included) of patients with Lynch syndrome with a known MMR mutation.
    • Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
    • Patients without colorectal cancer but with a family history meeting the Amsterdam (criteria detailed below) or Revised Bethesda criteria (criteria detailed below), when no affected family members have been tested for MMR mutations.
 
Pre- and post-test genetic counseling meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes as an adjunct to the genetic testing itself.
 
Amsterdam II Criteria (must meet all of the following)
 
    • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND
    • HNPCC-associated cancer involving at least 2 generations; AND
    • cancer in 1 or more affected relatives diagnosed before 50 years of age; AND
    • familial adenomatous polyposis excluded in any cases of colorectal cancer.
 
Revised Bethesda Criteria (may meet any of the following)
    • Individuals diagnosed with colorectal cancer before age 50; OR
    • Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR
    • Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR
    • Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age <50 years; OR
    • Individuals with colorectal cancer and colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors regardless of age.
  
Effective Prior to October 2010
Genetic testing to determine carrier status of the adenomatous polyposis coli gene (APC) may be considered medically necessary in the following subjects:
    • patients with greater than 20 colonic polyps; OR
    • in first-degree relatives (i.e., siblings, parents, offspring) of patients diagnosed with familial adenomatous polyposis (FAP).
 
Genetic testing to determine the carrier status of the HNPCC gene may be considered medically necessary in patients with colorectal cancer who meet either the Amsterdam II or revised Bethesda criteria, as described below:
 
Amsterdam II criteria (patients must meet all of the following):
    • three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis), 1 of whom is a first-degree relative of the other 2; AND
    • HNPCC-associated cancer involving at least 2 generations; AND
    • cancer in 1 or more affected relatives diagnosed before 50 years of age; AND
    • familial adenomatous polyposis excluded in any cases of colorectal cancer.
Modifications allow for small HNPCC families: these families must have 2 colorectal cancers in first-degree relatives involving at least 2 generations, with at least 1 individual diagnosed by age 55.
 
Revised Bethesda criteria (patients may meet any of the following):
    • Individuals diagnosed with colorectal cancer before age 50; OR
    • Individuals with HNPCC-related cancer, including synchronous and metachronous colorectal cancers or associated extracolonic cancers regardless of age; OR
    • Individuals with colorectal cancer with the MSI-H histology diagnosed in a patient less than age 60; OR
    • Individuals with colorectal cancer and 1 or more first-degree relatives with colorectal cancer and/or HNPCC-related extracolonic cancer; if one of the cancers was diagnosed at age <50 years; OR
    • Individuals with colorectal cancer and colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors regardless of age.
 
Genetic testing to determine the carrier status of the HNPCC gene may be considered medically necessary in patients without a history of colorectal cancer but who have a first- or second-degree relative with a known HNPCC mutation. Proceeding directly to genetic testing for HNPCC-related mutations may also be medically necessary in patients meeting the Amsterdam II criteria.
 
The microsatellite instability (MSI) test and the immunohistochemistry (IHC) test for expression of MLH1 and MSH2, may be considered medically necessary as a means of identifying which patients with colon cancer, who also meet Amsterdam or Bethesda criteria, should undergo HNPCC genetic testing. MSI and IHC testing may also provide some additional information when HNPCC genetic testing is inconclusive.
 
Pre- and post-genetic counseling may be considered medically necessary as an adjunct to the genetic testing itself.

Rationale:
This policy was originally developed in 2004 and has been updated regularly with a literature search. The rationale is replaced with a summary of the literature identified through a search of the literature through October 2012.
 
FAP Genetic Testing
A 1998 TEC Assessment on genetic testing for familial adenomatous polyposis (FAP) offered the following conclusions:
 
    • Genetic testing for FAP may improve health outcomes by identifying which currently unaffected at-risk family members require intense surveillance or prophylactic colectomy.
 
    • At-risk subjects are considered to be those with greater than 10 adenomatous polyps; or close relatives of patients with clinically diagnosed FAP or of patients with an identified APC mutation.
 
    • The optimal testing strategy is to define the specific genetic mutation in an affected family member and then test the unaffected family members to see if they have inherited the same mutation.
 
The additional policy information on attenuated FAP and on MYH-associated polyposis (MAP) diagnostic criteria and genetic testing is based on information from GeneReviews (Burt, 2009) and from several publications (Kastrinos, 2007; Lefevre, 2009; Avezzu, 2008; Balaguer, 2007)) that build on prior, cited research. In addition, GeneReviews (Burt, 2009) summarizes clinical FAP genotype-phenotype correlations that could be used to determine different patient management strategies. The authors of the review conclude, however, that there is not yet agreement about using such correlations to direct management choices.
 
Testing for the APC gene mutation, i.e., testing for FAP, is considered not medically necessary in those with classical FAP. This is not medically necessary because the genetic testing is not needed to make the diagnosis of FAP in these patients. Testing for the APC mutation has no role (no purpose) in the evaluation, diagnosis, or treatment of these patients where the diagnosis and treatment are based on the clinical presentation.
 
Lynch Syndrome and Colorectal Cancer Genetic Testing
The policy for Lynch syndrome genetic testing in colorectal cancer patients is based on an evidence report published by the Agency for Healthcare Research and Quality (AHRQ), (Bonis, 2007) a supplemental assessment to that report contracted by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, (Palomaki, 2009) and an EGAPP recommendation for genetic testing in colorectal cancer (EGAPP, 2009). Based on the AHRQ report and supplemental assessment, the EGAPP recommendation came to the following conclusions regarding genetic testing for MMR mutations in patients already diagnosed with colorectal cancer:
    • Family history, while important information to elicit and consider in each case, has poor sensitivity and specificity as a screening test to determine who should be considered for MMR mutation testing and should not be used as a sole determinant or screening test.
 
    • MSI [microsatellite instability] and IHC [immunohistochemical] screening tests for MMR mutations have similar sensitivity and specificity. MSI screening has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6 and a specificity of about 90% for all. It is likely that, using high-quality MSI testing methods, these parameters can be improved. IHC screening has a sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for all.
 
    • Optional BRAF testing can be used to reduce the number of patients, who are negative for MLH1 expression by IHC, needing MLH1 gene sequencing, thus improving efficiency without reducing sensitivity for MMR mutations.
 
    • A chain of indirect evidence can be constructed for the clinical utility of testing all patients with colorectal cancer for MMR mutations.
 
1. The chain of indirect evidence from well-designed experimental nonrandomized studies (as noted below) is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR mutation.
 
2. Seven studies examined how counseling affected testing and surveillance choices among unaffected family members of Lynch syndrome patients. About half of relatives received counseling, and 95% of these chose MMR gene mutation testing. Among those positive for MMR gene mutations, uptake of colonoscopic surveillance beginning at age 20–25 years was high at 53–100%.
 
        • One long-term, nonrandomized controlled study and one cohort study of Lynch syndrome family members found significant reductions in colorectal cancer among those who followed recommended colonic surveillance vs. those who did not.
        • Surveillance, prevention for other Lynch syndrome cancers (for detail, refer to last outline bullet)
 
3. The chain of evidence from descriptive studies and expert opinion (as noted below) is inadequate (inconclusive) to demonstrate the clinical utility of testing the probands with Lynch syndrome (i.e., cancer index patient).
 
          • Subtotal colectomy is recommended as an alternative to segmental resection, but has not been shown superior in follow-up studies
 
          • Although a small body of evidence suggests that MSI-positive tumors are resistant to 5-fluorouracil and more sensitive to irinotecan than MSI-negative tumors, no alteration in therapy according to MSI status has yet been recommended.
 
          • Surveillance, prevention for other Lynch syndrome cancers:
 
            1. While invasive and not actively recommended, women may choose hysterectomy with salpingo-oophorectomy to prevent gynecologic cancer. In one retrospective study, women who chose this option had no gynecologic cancer over 10 years, whereas about one-third of women who did not have surgery developed endometrial cancer, and 5.5% developed ovarian cancer
            2. In one study, surveillance endometrial biopsy detected endometrial cancer and potentially precancerous conditions at earlier stages in those with Lynch syndrome, but results were not statistically significant, and a survival benefit has yet to be shown (Bouzourene, 2010). Transvaginal ultrasound (TVUS) is not a highly effective surveillance mechanism for endometrial cancer in patients with Lynch syndrome; however, TVUS in conjunction with endometrial biopsy has been recommended for surveillance.
            3. Gastroduodenoscopy for gastric cancer surveillance and urine cytology for urinary tract cancer surveillance are recommended based on expert opinion only, in the absence of adequate supportive evidence.
 
Based on an indirect chain of evidence with adequate evidence of benefit to unaffected family members found to have Lynch syndrome, the EGAPP working group recommended testing all patients with colorectal cancer for MMR gene mutations.
 
In addition to DNA mismatch repair (MMR) gene mutation testing, evidence now supports testing for EPCAM deletions in particular cases where all MMR gene mutation testing is negative, but tumor MSH2 IHC indicates lack of expression, and tumor MSI testing shows a high level of instability. EPCAM is found just upstream, in a transcriptional sense, of MSH2. Deletions of EPCAM that encompass the last 2 exons of the EPCAM gene including the polyadenylation signal that normally ends transcription of DNA into messenger RNA result in transcriptional ‘read-through’ and subsequent hypermethylation of the nearby and downstream MSH2 promoter. This hypermethylation prevents normal MSH2 protein expression and leads to Lynch syndrome in a fashion similar to Lynch cases in which an MSH2 mutation prevents MSH2 gene expression. Several studies have characterized such EPCAM deletions, established their correlation with the presence of EPCAM-MSH2 fusion messenger RNAs (apparently non-functional) and with the presence of MSH2 promoter hypermethylation, and, most importantly, have shown the co-segregation of these EPCAM mutations with Lynch-like disease in families. (13, 24-28) Because studies differ slightly in how patients were selected, prevalence of these EPCAM mutations is difficult to estimate but may be in the range of 20-40% of patients/families who meet Lynch syndrome criteria, do not have a MMR mutation, but have MSI-high tumor tissue. Kempers et al. reported that carriers of an EPCAM deletion had a 75% (95% confidence interval [CI]: 65–85) cumulative risk of colorectal cancer by age 70 years, not significantly different from that of carriers of an MSH2 deletion (77% 64–90); mean age at diagnosis was 43 years. However, the cumulative risk of endometrial cancer was low at 12% (95% CI: 0–27) by age 70, compared to carriers of a mutation in MSH2 (51% [95% CI: 33–69], p=0.0006) (Kempers, 2011).
 
Grandval et al. selected 25 patients with tumors exhibiting complete loss of MSH2 protein but without a point mutation or genomic rearrangement of the MSH2 gene and found 7 cases of a deletion of the 3’ exon of EPCAM. Genetic testing was subsequently performed on 25 adult first-degree relatives of the 7 cases, and 12 relatives were found to be deletion carriers. Six additional relatives had deceased from Lynch-associated tumors, and 5 were obligate carriers. In summary, the risk to develop colorectal cancer was high, 93.1% (N=27/29) in deletion carriers older than 30 years of age (Grandval, 2012).
 
Although MMR gene sequencing of all patients is the most sensitive strategy, it is highly inefficient and cost-ineffective and not recommended. Rather, a screening strategy of MSI or IHC testing (with or without optional BRAF testing) is recommended and retains a relatively high sensitivity. Some evidence suggests that IHC requires particular training and experience (Overbeek, 2008). Although a particular strategy was not recommended by the EGAPP Working Group, several are potentially effective; efficiency and cost-effectiveness may depend upon local factors.
 
Previous recommendations have used family history as an initial screen to determine who should proceed further to MMR laboratory testing. Recent studies have shown that limiting laboratory testing to patients who met even the more sensitive Revised Bethesda criteria (i.e., compared to the Amsterdam II criteria) would miss as much as 28% of Lynch syndrome cases (Hampel, 2008; Canard, 2012). Family history is important for counseling families, but based on this and similar evidence, is not recommended as an initial screening tool to make decisions about testing patients who already have colorectal cancer. However, as noted in the policy statement, the Amsterdam II or Revised Bethesda criteria may be used in identifying those without colorectal cancer who might be tested.
 
Limiting testing for Lynch Syndrome on the basis of age (e.g., test only patients younger than age 50 years) is also not recommended. For example, Hampel et al. found that among 18 Lynch syndrome patients discovered among 500 unselected colorectal cancer patients, only 8 (44%) patients were diagnosed at age younger than 50 years (Hampel, 2008). Similarly, Canard et al. reported that restricting screening to patients younger than 50 years would have missed about half of patients eventually found to have Lynch syndrome (Canard, 2012). Another group screened colorectal cancer patients who were younger than age 60 and identified 98 likely (MSI-positive, BRAF negative) Lynch syndrome cases; of these, 47% were between ages 50 and 60 (Schofield, 2009).  A large study of Lynch syndrome family studies found that the cumulative risk of colorectal cancer in MMR mutation carriers was only 13% (95% CI: 9-19) by age 50, but 35% (95% CI: 25-49%) by age 70 (Bonadona, 2011). For MSH6 mutation carriers, however, colorectal cancer risks do not appear to increase until after age 60.
The estimated risk of stomach cancer in a large study of Lynch syndrome families was 6% (95% CI: 0.2-17%) for carriers of MLH1 mutations and warrants further study to address the utility of gastric surveillance (Bonadona, 2011).  
 
As the EGAPP recommendations noted, the evidence to date is limited to clearly support benefit from genetic testing to the index patient with colorectal cancer if found to have Lynch syndrome. However, professional societies have reviewed the evidence and concluded that genetic testing likely has direct benefits for at least some patients with colorectal cancer and Lynch syndrome on the basis of differing recommendations for post-surgical surveillance, and for those who choose prophylactic surgical treatment instead of surveillance. This policy is based on the evidence and professional society recommendations reviewed below.
 
In the absence of preventive surgery, heightened surveillance is recommended. The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer (NCCN, 2012) and for colorectal cancer screening (NCCN, 2012) recommend post-surgical colonoscopy at 1 year and, if normal, again in 2-3 years, then every 3-5 years based on findings. However, for Lynch syndrome patients, colonoscopy is recommended every 1 to 2 years throughout life based on the high likelihood of cancer for patients diagnosed with Lynch syndrome prior to a cancer diagnosis, and on the high likelihood of a second primary cancer in those diagnosed with Lynch syndrome based on a first cancer diagnosis (de Vos tot Nederveen Cappel, 2002). If the patient is not a candidate for routine surveillance, subtotal colectomy may be considered (NCCN, 2011).  
 
Early documentation of the natural history of colorectal cancer in highly selected families with a strong history of hereditary colorectal cancer indicated risks of synchronous and metachronous cancers as high as 18% and 24%, respectively (Fitzgibbons, 1987), in patients who already had colorectal cancer. As a result, in 1996, the Cancer Genetic Studies Consortium, a temporary National Institutes of Health ( NIH)-appointed body, recommended that if colorectal cancer is diagnosed in patients with an identified mutation or a strong family history, a subtotal colectomy with ileorectal anastomosis (IRA) should be considered in preference to segmental resection (Burke, 1997). Although the average risk of a second primary is now estimated to be somewhat lower overall (see Description) in patients with Lynch syndrome and colorectal cancer, effective prevention measures remain imperative. One study suggested that subtotal colectomy with IRA markedly reduced the incidence of second surgery for metachronous cancer from 28% to 6% but could not rule out the impact of surveillance (Van Dalen, 2003). A mathematical model comparing total colectomy and IRA to hemicolectomy resulted in increased life expectancies of 2.3, 1, and 0.3 years for ages 27, 47, and 67, respectively; for Duke’s A, life expectancies for the same ages are 3.4, 1.5, and 0.4, respectively (de Vos tot Nederveen Cappel, 2003). Based on this work, the joint American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) review of risk-reducing surgery in hereditary cancers recommends offering both options to the patient with Lynch syndrome and colorectal cancer, especially those who are younger (Guillem, 2006). This ASCO/SSO review also recommends offering Lynch syndrome patients with an index rectal cancer the options of total proctocolectomy with ileal pouch anal anastomosis or anterior proctosigmoidectomy with primary reconstruction. The rationale for total proctocolectomy is the 17% to 45% rate of metachronous colon cancer in the remaining colon after an index rectal cancer in Lynch syndrome patients.
 
Lynch Syndrome and Endometrial Cancer Genetic Testing
Recently, several groups have recommended screening endometrial cancer patients for Lynch syndrome. At the 2010 Jerusalem Workshop on Lynch Syndrome, (Boland, 2010) it was proposed that all incident case of endometrial cancer be screened for Lynch syndrome using mismatch repair-immunohistochemical (MMR-IHC) testing. Clarke and Cooper (Clarke, 2012) note that Sloan-Kettering Cancer Center screens all patients younger than 50 years of age with endometrial cancer using MMR-IHC; as well as patients older than 50 years with suggestive tumor morphology, lower uterine segment (LUS) location, personal/family history, or synchronous cell carcinoma of the ovary. Kwon et al. (Kwon, 2011) recommended MMR-IHC screening of women with endometrial cancer at any age with at least one first-degree relative with a Lynch syndrome-associated cancer.
 
The risk of endometrial cancer in MMR mutation carriers has been estimated at 34% (95% CI: 17-60%) by age 70, and of ovarian cancer 8% (95% CI: 2-39%) by age 70 (Bonadona, 2011). Risks do not appear to appreciably increase until after age 40.
 
In a recent prospective study, 179 consecutive endometrial cancer patients </=70 years of age were analyzed for microsatellite instability (MSI), by IHC for expression of 4 MMR proteins, MMR gene methylation status and BRAF mutations. Ninety-two percent of patients were older than 50 years of age.  Eleven endometrial cancer patients were found likely to have lynch syndrome (6%; 95% CI 3-11%), including 1 patient suspected of an MLH1, 2 of an MSH2, 6 of an MSH6 and 2 of a PMS2 gene defect. Germline mutation analyses revealed 7 MMR gene germline mutations. Ten patients likely to have lynch syndrome (92%) were older than 50 years. In addition, 31 sporadic MSI-H tumours with MLH1 promoter hypermethylation (17%; 95% CI 13-24%) were identified (Leenen, 2012).
Another study examined 625 endometrial cancer patients who underwent hysterectomy; endometrial cancer was classified as LUS in 9 patients (Masuda, 2012). Twenty-seven randomly chosen patients from the non-LUS group were compared to the LUS group, and no statistically significant differences were found between groups with regard to MSI status or IHC findings. The incidence of Lynch syndrome in the LUS group was 1 in 9 (Goodfellow, 2003; Hampel, 2006).  
 
Kwon et al. (Kwon, 2011) developed a Markov Monte Carlo simulation model to compare 6 strategies for Lynch syndrome testing in women with endometrial cancer. Overall, the results suggested that IHC triage at any age, in women with at least one first-degree relative (FDR) with a Lynch-associated cancer, was the most cost-effective strategy (incremental cost-effectiveness ratio [ICER]=$9126) for identifying Lynch syndrome and subsequent colorectal carcinoma (CRC) cases. The model used published prevalence estimates of Lynch syndrome in all endometrial cancer patients of 2% (range 1-3%), and of 17% (range 15-20%) in endometrial cancer patients with at least one FDR with a Lynch-associated cancer.
 
Female colon cancer survivors with Lynch syndrome (Obermair, 2010). This study also estimated that for every 100 women diagnosed with Lynch syndrome-associated colorectal cancer, about 23 will be diagnosed with endometrial cancer within 10 years absent a hysterectomy. Recent data on mutation-specific risks suggest that prophylactic gynecological surgery benefits for carriers of MSH6 mutations may offer less obvious benefits compared to harms as lifetime risk of endometrial cancer is lower than for carriers of MLH1 or MSH2 mutations, and lifetime risk of ovarian cancer is similar to the risk for the general population (Bonadona, 2011).  
 
However, in the case of EPCAM deletion carriers, 3 recent studies found 3 cases of endometrial cancer in 103 female carriers who did not undergo preventative hysterectomy (Kempers, 2011; Grandval, 2012; Lynch, 2011). Women with EPCAM deletions consequently have a lifetime risk of developing endometrial cancer decreased by 10-fold when compared to MMR gene-mutation carriers. This might support a clinical management scenario rather than prophylactic surgery (Grandval, 2012). An alternative to prophylactic surgery is surveillance for endometrial cancer using transvaginal ultrasound (TVUS) and endometrial biopsy. Evidence indicates that such surveillance significantly reduces the risk of interval cancers, but no evidence as yet indicates surveillance reduces mortality due to endometrial cancer (Auranen, 2011).  Surveillance in Lynch syndrome populations for ovarian cancer has not yet been demonstrated to be successful at improving survival (Auranen, 2011).  
 
Summary
Results of testing for the adenomatous polyposis coli (APC) mutation in individuals with a family history of familial adenomatous polyposis (FAP), or a known APC mutation in the family, lead to changes in surveillance and prophylactic treatment. For patients with a positive result, enhanced surveillance and/or prophylactic treatment will reduce the future incidence of colon cancer and improve health outcomes. Therefore, APC testing meets primary coverage criteria for patients with a family history of FAP or a known APC mutation in the family. A related familial polyposis syndrome, MUTYH-associated polyposis (MAP) syndrome, is associated with mutations in the MUTYH gene. Testing for this genetic mutation meets primary coverage criteria when the differential diagnosis includes both FAP and MAP, since distinguishing between the two leads to different management strategies. In some cases, Lynch syndrome may be part of the same differential diagnosis, depending on presentation.
 
A substantial portion of patients with colorectal cancer will be found to have Lynch syndrome, which is associated with mutations in the mismatch repair (MMR) gene. A positive genetic test for the MMR mutation can lead to enhanced surveillance, changes in recommendations about treatment options, and possible prophylactic treatment for other Lynch syndrome malignancies. Therefore, testing for Lynch syndrome in patients with newly diagnosed colorectal cancer and in patients at high risk for Lynch syndrome, defined by meeting the clinical criteria such as Amsterdam II or Revised Bethesda, meets primary coverage criteria.
 
Women with endometrial cancer are also at risk for Lynch syndrome, at a low prevalence; the prevalence is increased substantially when the population is limited to those (at any age) with a first-degree relative diagnosed with a Lynch-associated cancer. Those found to have a MMR mutation will also benefit from enhanced colorectal cancer surveillance and prophylactic treatments. Therefore, testing for Lynch syndrome in patients with newly diagnosed endometrial cancer who also have a first-degree relative diagnosed with a Lynch-associated cancer meets primary coverage criteria. The EPCAM mutation is less common than MMR mutations as a cause of Lynch syndrome and should be part of the diagnostic testing for Lynch syndrome in patients who are negative for all MMR mutations but who screen positive for microsatellite instability (MSI) and lack MSH2 immunohistochemistry evidence of protein expression.
 
Practice Guidelines and Position Statements
The European Society for Medical Oncology (ESMO) published clinical practice guidelines for familial colorectal cancer risk in 2010 (Balmana, 2010). These guidelines addressed Lynch Syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis. No specific recommendations were made regarding how to initially identify Lynch syndrome cases; several methods, including clinical criteria and universal screening of all CRC cases, were mentioned. Other ESMO recommendations are consistent with the information in this policy.
 
The National Comprehensive Cancer Network (NCCN) guideline for colorectal cancer screening notes that screening of all colorectal and endometrial cancers for Lynch syndrome mutations has been implemented at some centers and does not recommend for or against this practice (NCCN, 2011). The guideline does not specifically mention EPCAM deletion testing but does indicate that individuals with loss of MSH2 and/or MSH6 protein expression by immunohistochemistry, regardless of germline MMR mutation status, should be followed as though they have Lynch syndrome. These guidelines also address familial adenomatous polyposis (classical and attenuated), and MUTYH-associated polyposis, consistent with the information in this policy.
 
The American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO) recommends offering prophylactic total abdominal hysterectomy to female patients with colorectal cancer who have completed childbearing or to women undergoing abdominal surgery for other conditions, especially when there is a family history of endometrial cancer. This recommendation is based on the high rate of endometrial cancer in mutation-positive individuals and the lack of efficacy of screening (Guillem, 2006).  
 
2013 Update
This policy is updated with a literature search of the MEDLINE database through November 2013. The following is a summary of the key identified literature.  
 
In 2010, Bouzourene and collegues analyzed MLH1 protein abnormalities in 11 patients with sporadic colorectal carcinoma (CRC) and 16 patients with Lynch syndrome (Bouzourene, 2010). BRAF mutation was not found in any of the Lynch syndrome patients. MLH1 promoter methylation was only present in 1 Lynch syndrome patient. However, 8 of the 11 sporadic CRC patients had the BRAF mutation, and all 11 patients were MLH1 methylated, suggesting patients with BRAF mutations could be excluded from germline testing for Lynch syndrome. In 2013, Jin et al. evaluated MMR proteins in 412 newly diagnosed CRC patients (Jin, 2013). MLH1 and PMS2 protein stains were absent in 65 (72%) patients who were subsequently tested for BRAF mutation. Thirty-six (55%) patients were found to have the BRAF V600E mutation, thus eliminating the need for further genetic testing or counseling for Lynch syndrome.
 
In 2013, Capper et al. reported on a technique of VE1 IHC testing for BRAF mutations on a series of 91 MSI-H CRC patients (Capper, 2013). The authors detectedBRAF-mutated CRC with 100% sensitivity and 98.8% specificity. VE1 positive lesions were detected in 21% of MLH1-negative CRC patients who could be excluded from MMR germline testing for Lynch syndrome. Therefore, VE1 IHC testing for BRAF could be an alternative toMLH1 promoter methylation analysis.
 
To summarize, BRAF mutation V 600E or MLH1 promoter methylation testing are optional screening methods that may be used when IHC testing shows a loss of MLH protein expression by IHC testing forMLH1. The presence of BRAF V600E or absence of MLH1 protein expression due to MLH1 promoter methylation rarely occurs in Lynch syndrome and would eliminate the need for further germline mutation analysis for a Lynch syndrome diagnosis (Kastrinos, 2012). The coverage statement has been changed to address coverage of BRAF V600E or MLH1 promoter to exclude a diagnosis of Lynch syndrome when MLH1 protein is not expressed in a colorectal cancer on immunohistochemical (IHC) analysis.
  
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The National Comprehensive Cancer Network (NCCN) guidelines for recommend 2 approaches to Lynch syndrome mutation screening of either: (1) all newly diagnosed colorectal and endometrial cancers or (2) colorectal cancer patients diagnosed before age 70 and those ages 70 and older when meeting Bethesda guidelines (NCCN, 2014).  Additionally, the colorectal cancer screening guidelines also recommend screening for Lynch syndrome for all endometrial cancer patients younger than 50 years old. These guidelines note immunohistochemistry and sometimes microsatellite instability testing may be performed at some centers on all newly diagnosed colorectal and endometrial cancer patients to determine need for genetic testing for Lynch syndrome mutations regardless of family history. The guidelines note “evidence has shown 3 deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, are an additional cause of Lynch syndrome.”  Genetic testing is recommended for at-risk family members of patients with positive mutations in MLH1, MSH2, MSH6, or PMS2. The NCCN guidelines also indicate BRAF V600E testing or MLH1 promoter methylation testing may be used when MLH1 is not expressed in the tumor on IHC analysis to exclude a diagnosis of Lynch syndrome. As noted in the NCCN guidelines, “the presence of a BRAF mutation indicates MLH1 expression is downregulated by somatic methylation of the promoter region of the gene and not by germline mutation.” These guidelines also address familial adenomatous polyposis (classical and attenuated), and MUTYH-associated polyposis, consistent with the information in this policy.  
 
2016 Update
A literature search conducted through June 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
The evidence for genetic testing for the adenomatous polyposis coli (APC) mutation in individuals who have a clinical differential of attenuated FAP, MUTYH-associated polyposis (MAP), and Lynch syndrome, or at-risk relatives of patients with FAP includes a TEC Assessment. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. For patients with an APC mutation, enhanced surveillance and/or prophylactic treatment will reduce the future incidence of colon cancer and improve health outcomes. A related familial polyposis syndrome, MAP syndrome, is associated with mutations in the MUTYH gene. Testing for this genetic mutation is necessary when the differential diagnosis includes both FAP and MAP, because distinguishing between the two leads to different management strategies. In some cases, Lynch syndrome may be part of the same differential diagnosis, depending on presentation. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.
 
The evidence for genetic testing for MMR mutations in (1) individuals who have a clinical differential diagnosis of attenuated FAP, MAP, and Lynch syndrome, or (2) individuals who have colon cancer, or (3) individuals who have endometrial cancer and a first-degree relative diagnosed with a Lynch-associated cancer, or (4) individuals who are at-risk relatives of patients with Lynch syndrome, or (5) patients without colon cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, includes an Agency for Healthcare Research and Quality report, supplemental assessment to that report by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, and an EGAPP recommendation for genetic testing in CRC. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. A chain of indirect evidence from well-designed experimental nonrandomized studies is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR mutation, in that counseling has been shown to affect testing and surveillance choices among unaffected family members of Lynch syndrome patients. One long-term, nonrandomized controlled study and 1 cohort study of Lynch syndrome family members found significant reductions in CRC among those who followed recommended colonic surveillance versus those who did not. A positive genetic test for an MMR mutation can also lead to changes in management of other Lynch syndrome malignancies. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.
 
The evidence for genetic testing for EPCAM mutations in individuals who have CRC in which MMR testing is negative for all MMR mutations but who screen positive for microsatellite instability and lack MSH2 immunohistochemical evidence of protein expression includes mutation prevalence studies and case series. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. Studies have shown an association between EPCAM mutations and Lynch-like disease in families and the cumulative risk for CRC is similar to carriers of an MSH2 mutation. Identification of an
EPCAM mutation could lead to changes in management that lead to improved health outcomes. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.
 
The evidence for genetic testing for BRAF V600E or MLH1 promoter methylation in individuals who have CRC but in whom MLH1 protein is not expressed on immunohistochemical analysis includes a few case series. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. Studies have shown, with high sensitivity and specificity, an association of BRAF V600E mutation or MLH1 promoter methylation with sporadic CRC. Therefore, this type of testing could eliminate the need for further genetic testing or counseling for Lynch syndrome. The evidence is sufficient to determine quantitatively that the technology results in a meaningful improvement in the net health outcome.
 
American College of Gastroenterology
The American College of Gastroenterology (ACG) issued practice guidelines for the management of patients with hereditary gastrointestinal cancer syndromes (Syngal, 2015).
 
  • Lynch Syndrome (LS)
 
ACG recommends that all newly diagnosed colorectal cancers should be evaluated for mismatch repair deficiency, and that analysis may be done by immunohistochemical (IHC) testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for microsatellite instability; tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis for MLH1 promoter hypermethylation. Individuals who have a personal history of a tumor showing evidence of mismatch repair deficiency (and no demonstrated BRAF mutation or hypermethylation of MLH1), a known family mutation associated with LS, or a risk of ≥5% chance of LS based on risk prediction models should undergo genetic evaluation for LS 60. Genetic testing of patients with suspected LS should include germline mutation genetic testing for the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes or the altered gene(s) indicated by IHC testing.
 
  • Adenomatous polyposis syndromes
 
Familial adenomatous polyposis (FAP)/MUTYH-associated polyposis/attenuated polyposis
Individuals who have a personal history of >10 cumulative colorectal adenomas, a family history of one of the adenomatous polyposis syndromes, or a history of adenomas and FAP-type extracolonic manifestations (duodenal/ampullary adenomas, desmoid tumors, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium, epidermal cysts, osteomas) should undergo assessment for the adenomatous polyposis syndromes.
 
Genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analysis.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
A chain of evidence can be constructed for the clinical utility of testing all patients with CRC for MMR variants. EGAPP conclusions are summarized next.
1. The chain of evidence from well-designed experimental nonrandomized studies is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR variant.
2. Seven studies examined how counseling affected testing and surveillance choices among unaffected family members of Lynch syndrome patients (Hampel, 2005; Aktan-Collan, 2000; Aktan-Collan, 2007; Stanley, 2000; Hadley, 2003; Lerman, 1999; Codori, 1999). About half of relatives received counseling, and 95% of these chose MMR gene variant testing. Among those positive for MMR gene variants, uptake of colonoscopic surveillance beginning at age 20 to 25 years was high at 53% to 100%.
o One long-term, nonrandomized controlled study and a cohort study of Lynch syndrome family members found significant reductions in CRC among those who followed recommended colonic surveillance vs those who did not.
o Surveillance, prevention for other Lynch syndrome cancers.
 
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American Society of Clinical Oncology and Society of Surgical Oncology
In 2015, the American Society of Clinical Oncology concluded that the European Society for Medical Oncology clinical practice guideline published in 2013 were based on the most relevant scientific evidence and therefore endorsed them with minor qualifying statements (ASCO, 2015). The recommendations as relate to genetic testing hereditary CRC syndromes are summarized below:
    • “Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all CRC patients. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines.
    • If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.
    • If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (eg, MSH2, MSH6, EPCAM, PMS2, or MLH1).  
    • Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis…
    • Patients with multiple colorectal adenomas should be considered for full germline genetic testing of APC and/or MUTYH.
    • Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered.”
 
2018 Update
A literature search was conducted through September 2018.  The key identified literature is summarized below.
 
GENETIC TESTING FOR JUVENILE POLYPOSIS SYNDROME AND PEUTZ-JEGHERS SYNDROME:
 
Clinical Context and Test Purpose
The purpose of genetic testing for juvenile polyposis syndrome (JPS) and Peutz-Jeghers syndrome (PJS) is:
    • To confirm a diagnosis of JPS or PJS in patients suspected of these disorders based on clinical features
    • To identify at-risk relatives of patients with a confirmed diagnosis of JPS or PJS.
 
The questions addressed in this evidence review are: (1) Is there evidence that genetic testing for patients suspected of JPS and PJS has clinical validity?; and (2) Does genetic testing for JPS and PJS change patient management in a way that improves outcomes as a result of genetic testing?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant populations of interest are patients with suspected JPS or PJS and individuals who are at risk relatives of patients suspected of or diagnosed with a JPS or PJS.
 
Interventions
The relevant intervention is genetic testing for SMAD4 and BMPR1 (for JPS) and ASATK11 (for PJS).
Commercial testing is available from numerous companies.
 
Comparators
The following practice is currently being used to make decisions about managing JPS and PJS: no genetic testing.
 
Outcomes
The potential beneficial outcomes of primary interest would be early detection of cancer and appropriate and timely interventional strategies (eg, cancer screening, surgical intervention including polyp resection, gastrectomy, colectomy) to prolong life.
 
The potential harmful outcomes are those resulting from a false test result. False-positive or false-negative test results can lead to the initiation of unnecessary treatment and adverse events from that treatment or under-treatment.
 
Timing
Genetic testing for SMAD4 and BMPR1 (for JPS) and ASATK11 (for PJS) may be performed at any point during a lifetime. The necessity for genetic testing is guided by the availability of information that alters the risk of an individual of having or developing JPS and PJS.
 
Setting
Ordering and interpreting genetic testing may be complex and is best done by experienced specialists such as gastroenterologists. Most patients are likely to be tested in an outpatient setting. Referral for genetic counseling is important for the explanation of genetic disease, heritability, genetic risk, test performance, and possible outcomes.
 
Study Selection Criteria
For the evaluation of clinical validity of the genetic test, studies that met the following eligibility criterion were considered:
    • Reported on the diagnostic yield of the test.
 
Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
 
Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
 
Section Summary: Clinically Valid
The likelihood of detecting a pathogenic variant is highly dependent on the presence of clinical features and family history. Detection rates for JPS and PJS have been reported to be between 60% and 41% and
29.4% and 80%, respectively.
 
Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
 
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.
 
No RCTs were identified assessing the clinical utility of genetic testing for JPS and PJS.
 
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
 
Genetic testing of patients with suspected JPS and PJS has clinical utility:
    • To make decisions about a preferred approach for treatment (endoscopic resection, colectomy with ileorectal anastomosis, segmental colectomy).
 
Genetic testing of individuals who are at-risk relatives of patients suspected of or diagnosed with JPS or
PJS has clinical utility:
    • If the individuals diagnosed with JPS and PJS are recommended for screening for JPS and PJS associated cancers.
    • If, in the absence of genetic testing, the diagnosis of JPS and PJS in at-risk relatives of patients can only be established by colonoscopy and subsequent histologic examination of excised polyps, which is burdensome.
    • If negative test results prompt release from an intensified screening program, thereby reducing in emotional burden.
 
Section Summary: Clinically Useful
Direct evidence of the clinical utility for genetic testing of JPS or PJS is not available. Genetic testing of patients with suspected JPS or PJS or individuals who are at-risk relatives of patients suspected of or diagnosed with a polyposis syndrome or PJS may have clinical utility by avoiding burdensome and invasive endoscopic examinations, release from intensified screening program resulting in psychological relief, and may improve health outcomes by identifying currently unaffected at-risk family members who require intense surveillance or prophylactic colectomy (Yang, 2010; Calva-Cerqueira, 2009; Aretz, 2007; Volikos, 2006; Aretz, 2005; Aytac, 2015; Resta, 2013; Salloch, 2010).

CPT/HCPCS:
81201APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence
81202APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants
81203APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants
81210BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
81288MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
81292MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81293MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81294MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81295MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81296MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81297MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81298MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81299MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81300MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81301Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
81317PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81318PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81319PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81435Hereditary 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
81436Hereditary 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

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