Code Description CPT
81201 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence
81202 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants
81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants
81210 BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V600E variant
81288 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
81292 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81293 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81294 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81295 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81296 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants
81297 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants
81298 MSH2 (muts honolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, full sequence analysis
81299 MSH6 (muts honolog 6 [e. coli]) (eg, hereditary non-polyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants
81300 MSH6 (muts honolog 6 [e. coli]) (eg, hereditary non-polyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants
81301 Microsatellite 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
81317 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, full sequence analysis
81318 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, known familial variants
81319 PMS2 (postmeiotic segregation increased 2 [ s. cerevisiae]) (eg, hereditary nonpolyposis colorectal cancer, lynch syndrome) gene analysis, duplication/deletion variants
81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)
81435 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2
81436 Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH
Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
Introduction
Five to ten percent of all cancers may be inherited. Several genes have been identified that are associated with colon cancer and are passed from parents to children. Genetic testing may help determine the risk of colon cancer in family members and guide the frequency of colon cancer screening tests. This policy describes when those tests are covered based on the latest scientific studies. Some of these tests need to be pre-approved by the health plan. See Coverage Criteria for more specific information.
Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a service may be covered.
Testing Medical Necessity Lynch Syndrome(Also known as hereditary non-polyposis colorectal cancer or HNPC)
Initial screening Screening for Lynch syndrome as an initial evaluation of tumor tissue: * ALL cases of colorectal cancer, regardless of age screened for
Genetic testing (eg, COLARIS® (Myriad))
Lynch Syndrome using either microsatellite instability (MSI) or immunohistochemical (IHC), with or without BRAF/MLH1 promoter methylation testing, may be considered medically necessary as an initial evaluation of tumor tissue .
Note: MSI/IHC testing prior to actual genetic testing for Lynch syndrome is recommended, but not required.
Genetic testing for Lynch syndrome (MLH1, MSH2, MSH6, PMS2 sequence analysis) may be considered medically necessary when the member meets ANY ONE of the following criteria: * A colon cancer diagnosis with a positive result from MSI/IHC
test (see Lynch syndrome initial screening, above) OR * Colorectal carcinoma (CRC) diagnosed in a patient who is less
than 50 years old OR * Endometrial cancer diagnosed in a patient who is less than 50
years old OR * All of the Amsterdam II clinical criteria are met (see below) OR * One of the revised Bethesda guidelines are met (seebelow) OR * One first-degree or second-degree relative* with a Lynch
syndrome mutation (genes MLH1, MSH2, MSH6, PMS2) OR * Personal history of endometrial cancer diagnosed at age 51-60
and one first-degree relative diagnosed with a Lynchassociated cancer.**
*For the purposes of familial assessment, first- or second-degree relatives are blood relatives on the same side of the family (maternal or paternal). The maternal and paternal sides of the
Testing Medical Necessity
family should be considered independently for familial patterns of cancer. *First-degree relatives are parents, siblings, and offspring. Second-degree relatives are aunts, uncles, grandparents, niece, nephews or half-siblings.
**Lynch-associated cancers include colorectal, endometrial, gastric, ovarian, pancreas, bladder, ureter and renal pelvis, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome.
Genetic testing for Lynch syndrome is considered investigational when the member has not met at least one of the criteria listed above.
Familial Adenomatous Polyposis (FAP) and Associated Variants
Adenosis polyposis coli (APC) (eg, Colaris AP® (Myriad))
MYH/MUTYH-Associated Polyposis (MAP)
Adenosis polyposis coli (APC) genetic testing is considered medically necessary for ANY ONE of the following indications: * Personal history of greater than 10 cumulative colonic
adenomatous polyps OR * One first-degree relative diagnosed with familial adenomatous
polyposis (FAP) or with a documented APC mutation. o If feasible, the specific APC mutation should be identified in
the affected first-degree relative with FAP prior to testing the member see (see below).
o “Full sequence” APC genetic testing is considered medically necessary only when the affected family member is unavailable or unwilling to be tested.
Note: First-degree relatives are parents, siblings, and offspring.
APC genetic testing is considered investigational when the member has not met at least one of the criteria listed above.
MYH/MUTYH-Associated Polyposis (MAP) Genetic Testing may be considered medically necessary for ANY ONE of the following indications: * Personal history of 10 to 20 cumulative adenomatous polyps,
OR
with negative APC mutation testing and no family history of adenomatous polyposis
Genetic Counseling
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
General Guidelines for Lynch and FAP Syndromes
1. Testing may be done to distinguish between a diagnosis of Lynch syndrome versus Familial Adenomatous Polyposis (FAP). Whether testing begins with the “MLH1, MSH2, MSH6, PMS2” mutations or the “APC” mutations depends upon the clinical presentation.
2. In ideal situations, initial genetic testing for FAP or Lynch syndrome is performed in an affected family member so that testing in unaffected family members can focus on the mutation found in the affected family member. When this was not done, the following guidelines apply.
Lynch-Specific Guidelines
1. For patients with colorectal cancer being evaluated for Lynch syndrome, it is recommended that either the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test, with or without BRAF gene mutation testing, be used as an initial evaluation of tumor tissue prior to MLH1, MSH2, MSH6, PMS2 sequence analysis. (Note that MSI/IHC testing may not be feasible if no tumor tissue is available.) Consideration of proceeding to MLH1, MSH2, MSH6, PMS2 sequencing would depend on the results of MSI or IHC testing. IHC testing in particular may help direct which Lynch syndrome gene likely contains a mutation, if any, and may also provide some additional information if Lynch syndrome genetic testing is inconclusive.
2. Several Clinical Laboratory Improvement Amendments (CLIA)*licensed clinical laboratories offer gene mutation testing for Lynch syndrome. The GeneTests website (available online at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2622*db=genete sts) lists 21 U.S.-located laboratories that offer this service. Lynch syndrome mutation testing is packaged under a copyrighted name by at least one of these. 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. Two versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing) are available. 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.
3. Amsterdam II clinical criteria are the most stringent criteria for defining families at high risk for Lynch syndrome. ALL of the following criteria must be fulfilled:
o 3 or more relatives have been diagnosed with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis)
o 1 of the 3 should be a first-degree relative of the other 2
o 2 or more successive generations are affected
o 1 or more relatives were diagnosed before the age of 50 years
o Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma
o Tumors should be verified by pathologic examination
o Modifications:
* EITHER: very small families, which cannot be further expanded, can be considered to have HNPCC with only 2 colorectal cancers in first-degree relatives if at least 2 generations have the cancer and at least 1 case of colorectal cancer was diagnosed by the age of 55 years;
OR
* In families with 2 first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.
4. The revised Bethesda guidelines are less strict than the Amsterdam criteria and are intended to increase the sensitivity of identifying at-risk families. The Bethesda guidelines are also felt to be more useful in identifying which patients with colorectal cancer should have their tumors tested for microsatellite instability and/or immunohistochemistry. Fulfillment of any of the following criterion meets guidelines:
o Colorectal carcinoma (CRC) diagnosed in a patient who is less than 50 years old
o Presence of synchronous (at the same time) or metachronous (at another time, i.e., a recurrence of) CRC or other Lynch syndrome*associated tumors, regardless of age
o CRC with high microsatellite instability histology diagnosed in a patient less than 60 years old
o CRC diagnosed in 1 or more first-degree relatives with a Lynch syndrome-associated tumor,( colorectal, endometrial, gastric, ovarian, pancreas, bladder, ureter and renal pelvis, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir- Torre syndrome) with one of the cancers being diagnosed at younger than 50 years of age
o CRC diagnosed with 1 or more first-degree relatives with an HNPCC-related tumor (colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain [usually glioblastoma as seen in Turcot syndrome], sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel), with one of the cancers being diagnosed at younger than age 50 years, OR CRC diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumor, regardless of age
Description
Genetic testing is available for both affected individuals and those at risk for various types of hereditary cancer. This review evaluates genetic testing for hereditary colorectal cancer and polyposis syndromes, including familial adenomatous polyposis, Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), MUTYH-associated polyposis, and Lynch syndrome*related endometrial cancer.
Background Hereditary Colorectal Cancers
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).
Familial Adenomatous Polyposis (FAP) 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 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 extra-intestinal 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), characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP.
In AFAP, colorectal cancer occurs at an average age of 50-55 years, but there is a high lifetime risk of colorectal cancer of about 70% by age 80 years. The risk of extra-intestinal cancer is lower in AFAP compared to classical FAP, but it is still high at an estimated cumulative lifetime risk of 38% compared to the general population.
Only 30% or fewer of AFAP patients have APC mutations. Instead, some of these patients 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. Bi-allelic MUTYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas mono-allelic MUTYH mutation-associated risk of
colorectal cancer appears to be relatively minimal, although it is still under debate.
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 bi-allelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary according to the syndrome
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 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 an increased risk of developing colorectal cancer by age 70. After correction for ascertainment bias, the risk is approximately 27% to 45% for men, and 22% to 38% for women.
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 syndromerelated cancers is markedly lower for carriers of a mutation in the MSH6 and PMS2 genes, although for most cancers it is still significantly higher than that of the general population.
