CAM 169

Lynch Syndrome Testing

Category:Laboratory   Last Reviewed:April 2019
Department(s):Medical Affairs   Next Review:April 2020
Original Date:May 2017    

Description
Lynch syndrome (LS) (also known as hereditary non-polyposis colorectal cancer; HNPCC) is the most common form of hereditary colorectal (CRC) and endometrial cancers (EMC), resulting from an autosomal dominant inactivation of any of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) leading to microsatellite instability (MSI) (Rumilla et al., 2011) and associated with an increased risk of colorectal, endometrial, stomach, small bowel and ovarian cancers (Hunter et al., 2015; Lynch et al., 2009; Moreira et al., 2012).

Background 
Lynch syndrome (LS) is recognized by a hereditary predisposition to colorectal, endometrial and other cancers. It accounts for approximately 1% to 3% of all colorectal cancers and 2% to 5% of endometrial cancers (Hampel et al., 2005). In addition to colorectal and endometrial cancers, patients may present with ovarian, urinary tract, stomach, small bowel, hepatobiliary, sebaceous gland and central nervous system neoplasms (Barrow, Khan, Lalloo, Evans & Hill, 2013).

Inactivation by germline mutations or epigenetic silencing in any of four DNA mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) is known to result in Lynch syndrome (Jansen, Menko, Brosens, Giardiello & Offerhaus, 2014). Mutations of the upstream EPCAM gene, which result in silencing of the MSH2 gene, produce a phenotype very similar to LS (Ligtenberg et al., 2009). Mutations in MLH1 and MSH2 are most common (90%) followed by MSH6 (10%) and PMS2 (6% ) (Jansen et al., 2014).

The lifetime risk of CRC is greatly increased in LS patients, but varies significantly from 10-74%, depending on which MMR gene is inactivated (Brosens, Offerhaus & F, 2015). Average age at CRC diagnosis in LS patients is 44 to 61 years, with tumors primarily arising proximal to the splenic flexure (Giardiello et al., 2014b). There is also a high rate of metachronous CRC (16% at 10 years; 41% at 20 years) in LS patients (Win et al., 2013). The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes and a lymphoid host response to tumor (Peltomäki PT, 2010). LS patients have improved survival rates compared to similar stage spontaneous CRC (Brosens et al., 2015). Lifetime risk of endometrial cancer is significantly increased to 15 – 71% in women with mutation-specific variability (Giardiello et al., 2014b). Increased lifetime risk has also been observed in urinary, ovarian, stomach, hepatobiliary, small bowel, brain, pancreatic and prostate cancers (Brosens et al., 2015).

Several sets of clinical criteria have been developed to identify patients with LS. In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (HNPCC) established criteria (Amsterdam I Criteria) for HNPCC (Vasen, Mecklin, Khan & Lynch, 1991), which were updated to be more sensitive in 1999 (Vasen, Watson, Mecklin & Lynch, 1999). The Revised Bethesda Guidelines are a third set of clinicopathologic criteria developed in 2004 to improve identification of individuals who deserve investigation for LS (Umar et al., 2004).

However, as use of clinical criteria and modeling to identify patients with LS has less than optimal sensitivity and efficiency, universal screening for LS (Cohen et al., 2016; Kidambi et al., 2015) has been recommended (Provenzale et al., 2016). Analysis by immunohistochemical testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or MSI testing are commonly used to screen for LS phenotypes (Syngal et al., 2015). Tumors with loss of MLH1 should undergo analysis to exclude BRAF mutation or MLH1 promoter hypermethylation (Giardiello et al., 2014a). Patients with evidence of LS should be referred for genetic evaluation (EGAPP, 2009; Robson et al., 2015; Sepulveda et al., 2017).

Cancer Risks in Individuals with Lynch Syndrome Age ≤ 70 Years Compared to the General Population (Brosens et al., 2015)

Cancer Type General Population Risk Lynch Syndrome (MLH1 and MSH2 heterozygotes)
Risk Mean Age of Onset
Colon 4.8% 52%-82%

44-61 years

Endometrium

2.7%

25%-60%

48-62 years

Stomach

<1%

6%-13%

56 years

Ovary

1.4%

4%-12%

42.5 years

Hepatobiliary tract

<1%

1.4%-4%

Not reported

Urinary tract

<1%

1%-4%

~55 years
Small bowel

<1%

3%-6%

49 years

Brain/central nervous system

<1%

1%-3%

~50 years
Sebaceous neoplasms

<1%

1%-9%

Not reported

Regulatory Status
On October 27, 2017 the FDA approved VENTANA MMR IHC Panel for patients diagnosed with colorectal cancer (CRC) to detect mismatch repair (MMR) proteins deficiency as an aid in the identification of probable Lynch syndrome and to detect BRAFV600E protein as an aid to differentiate between sporadic CRC and probable Lynch syndrome.

Additionally, many labs have developed specific tests that they must validate and perform in house.  These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88).  As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy 
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request 

  1. Genetic counseling is considered MEDICALLY NECESSARY for individuals undergoing Lynch Syndrome (LS) testing.  Genetic counseling is required prior to undergoing testing for LS testing.
  2. Testing for a known deleterious LS mutation is considered MEDICALLY NECESSARY for individuals when a familial mutation is identified in a tissue specimen of an affected family member. Risk assessment should be limited to testing for the known familial mutation and not for other mutations.
  3. If no known LS mutation AND colorectal or endometrial tumor tissue is available, then tumor testing with immunohistochemistry (IHC) and/or microsatellite instability (MSI) is considered MEDICALLY NECESSARY for an individual meeting criteria in Note 1.
    • LS-specific testing or multi-gene testing as a universal testing strategy without IHC or MSI is considered NOT MEDICALLY NECESSARY for individuals if no known familial LS mutation and colorectal (or endometrial) tumor tissue is available.
  4. If no known LS mutation AND sufficient colorectal or endometrial tumor tissue is NOT available, then LS-specific testing—MLH1, MSH2, MSH6, PMS2, and EPCAM—OR multi-gene testing that includes concurrent testing of MLH1, MSH2, MSH6, PMS2, and EPCAM is considered MEDICALLY NECESSARY for an individual meeting criteria in Note 1For expanded panel testing, please refer to policy AHS-M2109 Molecular Panel Testing of Cancers to Identify Targeted Therapy.
  5. When predictive testing is offered to an individual, the following limitations apply:
    • Testing of the tumor of the affected family member should occur first, if possible, to identify a familial mutation. 
    • When a familial mutation is identified in a tissue specimen of an affected family member, other family members being offered predictive testing for risk assessment should be limited to testing for the known familial mutation, and not for other mutations.
    • Individuals, in whom deleterious mutations are found, should be counseled on their risk of developing cancer or having a recurrence of cancer, and offered a plan for increased surveillance and intervention, if warranted.
    • Genetic testing for Lynch Syndrome is limited to once per lifetime, unless testing for additional clinically relevant mutations is warranted.
  6. Genetic testing for susceptibility to colorectal cancer is considered INVESTIGATIONAL for all other purposes, including, but not limited to, testing of the general population. 

Note 1: According to the criteria for the evaluation of Lynch Syndrome according to the NCCN guidelines version 1.2018, an individual must meet at least one of the following (NCCN, 2018): 

  1. An individual with colorectal or endometrial cancer and any of the following:
    • Diagnosed before the age of 50 years
    • Another synchronous or metachronous LS-related cancer (See Note 2)
    • At least one first-degree or second-degree relative with LS-related cancer diagnosed by the age of 50 years (See Note 2)
    • At least two first-degree or second-degree relatives with LS-related cancers regardless of age (See Note 2)
  2. An individual with colorectal or endometrial cancer at any age with tumor showing evidence of mismatch repair (MMR) deficiency, either by microsatellite instability (MSI) or loss of MMR protein expression (See Note 3)
  3. Family history of any of the following:
    • At least one first-degree relative with colorectal or endometrial cancer diagnosed by the age of 50 years
    • At least one first-degree relative with colorectal or endometrial cancer AND another synchronous or metachronous LS-related cancer (See Note 2)
    • At least two first-degree or second-degree relatives with LS-related cancer (See Note 2) AND at least one of the relatives must be diagnosed by the age of 50 years
    • At least three first-degree or second-degree relatives with LS-related cancers (See Note 2), regardless of age
  4. An individual with a LS-related cancer (See Note 2) or unaffected individual with at least a 5% risk of having an MMR gene mutation based on predictive models (PREMM5, MMRpro, MMRpredict)
  5. An individual with a colorectal tumor with MSI-high (MSI-H) histology—i.e. presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern—diagnosed by the age of 60 years.

Note 2:  According to the NCCN, “LS-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, brain (usually glioblastoma), biliary tract, small intestinal cancers, as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas as seen in Muir-Torre syndrome (NCCN, 2018).”

Note 3:  According to the NCCN, “Tumor screening for MMR deficiency is appropriate for all colorectal and endometrial cancers regardless of age at diagnosis, however, germline genetic testing is generally reserved for patients with early age at diagnosis; positive family history; or abnormal tumor testing results: MSI or loss of MMR protein expression (NCCN, 2018).”  

Policy Gudielines 
If the tumor of the affected individual (self or family member) is available, consider initial testing of the tumor with immunohistochemistry (IHC) and/or microsatellite instability (MSI) tests.

* Germline Lynch syndrome genetic testing may include testing of the gene(s) that are indicated (based on plausible eitiologies) by the abnormal tumor test result, or instead, multi-gene testing that includes MLH1, MSH2, MSH6, PMS2, and EPCAM concurrently may be performed.

Rationale
Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group 
In 2009, the EGAPP Working Group recommended (EGAPP, 2009): 

  1. Offering genetic testing for Lynch Syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives.  However, they do not recommend a specific testing protocol.
  2. That individuals with newly diagnosed CRC should be routinely offered counseling and educational materials aimed at informing them and their relatives of the potential beneļ¬ts and harms associated with genetic testing to identify Lynch Syndrome.  
  3. “Microsatellite instability (MSI) testing or immunohistochemical (IHC) testing (with or without BRAF mutation testing) of the tumor tissue are examples of preliminary testing strategies that could be used to select patients for subsequent diagnostic testing. Diagnostic testing involves MMR gene mutation (and deletion/duplication) testing of the proband, usually using a blood sample. Lynch syndrome is most commonly caused by mutations in the two MMR genes MLH1 and MSH2; less commonly by mutations in MSH6 and PMS2.” 

National Comprehensive Cancer Network (NCCN) 
Genetic/Familial High-Risk Assessment: Colorectal Version 1.2018 (NCCN, 2018)
The NCCN lists the following criteria for the evaluation of Lynch Syndrome:

  • “Known LS mutation in the family
  • An individual with colorectal or endometrial cancer and any of the following:
    • Diagnosed <50y
    • Another synchronous or metachronous LS-related cancer
    • ≥1 first-degree or second-degree relative with LS-related cancer diagnosed <50y
    • ≥2 first-degree or second-degree relatives with LS-related cancers regardless of age
  • An individual with colorectal or endometrial cancer at any age with tumor showing evidence of mismatch repair (MMR) deficiency, either by microsatellite instability (MSI) or loss of MMR protein expression
  • Family history of any of the following:
    • ≥1 first-degree relative with colorectal or endometrial cancer diagnosed <50y
    • ≥1 first-degree relative with colorectal or endometrial cancer and another synchronous or metachronous LS-related cancer
    • ≥2 first-degree or second-degree relatives with LS-related cancer, including ≥1 diagnosed <50y
    • ≥3 first-degree or second-degree relatives with LS-related cancers, regardless of age
  • An individual with a LS-related cancer or unaffected individual with a ≥5% risk of having an MMR gene mutation based on predictive modes (PREMM5, MMRpro, MMRpredict)
  • An individual with colorectal tumor with MSI-high (MSI-H) histology (ie, presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern) diagnosed ≤60 y”. 

The NCCN considers LS-related cancers to “include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, brain (usually glioblastoma), biliary tract, small intestinal cancers, as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas as seen in Muir-Torre syndrome.” 

The NCCN also specifically states the following: “Tumor screening for MMR deficiency is appropriate for all colorectal and endometrial cancers regardless of age at diagnosis, however, germline genetic testing is generally reserved for patients with early age at diagnosis; positive family history; or abnormal tumor testing results: MSI or loss of MMR protein expression (NCCN, 2018).” 

The 2018 version 1 guidelines do not recommend multi-gene testing under the following circumstances:

  1. “there is an individual from a family with a known mutation and there is no other reason for multi-gene testing;
  2. the patient’s family history is strongly suggestive of a known hereditary syndrome; and,
  3. the patient is diagnosed with CRC with MSI or loss of one or more DNA MMR proteins (NCCN, 2018).” 

Multigene testing may be considered in the following scenarios:

  • “A patient with a personal or family history that meets criteria for >1 hereditary cancer syndrome (eg, Lynch syndrome and BRCA-related breast and/or ovarian cancer)
  • Colonic polyposis with uncertain histology
  • Adenomatous polyposis (specific to APC, MUTYH, POLE, and POLD1)
  • Family history does not meet criteria for established testing guidelines but there is suspicion of hereditary cancer, and an appropriate panel is available
  • Family history is limited or unknown, but patient has concerns about hereditary cancer
  • As second-line testing when first-line testing is inconclusive (NCCN, 2018)”. 

National Institute for Health and Care Excellence (NICE) 
NICE, in 2017, released their guidelines concerning molecular testing for LS in people with CRC.  The recommend the following (NICE, 2017):

  • “Offer testing to all people with colorectal cancer, when first diagnosed, using immunohistochemistry for mismatch repair proteins or microsatellite instability testing to identify tumours with deficient DNA mismatch repair, and to guide further sequential testing for Lynch syndrome... Do not wait for the results before starting treatment.
  • “If using immunohistochemistry, follow the steps in table 1.”

Table 1: Steps in the immunohistochemistry testing strategy (NICE, 2017)

Step 1

Do an immunohistochemistry 4-panel test for MLH1, MSH2, MSH6 and PMS2.

Step 2

If the MLH1 immunohistochemistry result is abnormal, use sequential BRAF V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF V600E test.

If the MSH2, MSH6 or PMS2 immunohistochemistry results are abnormal, confirm Lynch syndrome by genetic testing of germline DNA.

Step 3

If the BRAF V600E test is negative, do an MLH1 promoter hypermethylation test.

Step 4

If the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA.

  • If using microsatellite instability testing, follow the steps in table 2.” 

Table 2: Steps in the microsatellite instability testing strategy (NICE, 2017)

Step 1

Do a microsatellite instability test.

Step 2

If the microsatellite instability test result is positive, use sequential BRAF V600E and MLH1 promoter hypermethylation testing to differentiate sporadic and Lynch syndrome-associated colorectal cancers. First do a BRAF V600E test.

Step 3

If the BRAF V600E test is negative, do an MLH1 promoter hypermethylation test

Step 4

If the MLH1 promoter hypermethylation test is negative, confirm Lynch syndrome by genetic testing of germline DNA.

  • “Healthcare professionals should ensure that people are informed of the possible implications of test results for both themselves and their relatives, and ensure that relevant support and information is available. Discussion of genetic testing should be done by a healthcare professional with appropriate training (NICE, 2017).” 

American Society of Clinical Oncology (ASCO) 
The American Society of Clinical Oncology (ASCO) recommends that “genetic testing only be conducted in the setting of pre- and post-test counseling”(Robson, Storm, Weitzel, Wollins, & Offit, 2010). In 2015, ASCO stated that “identifying inherited mutations in genes such as BRCA1BRCA2, and the genes associated with Lynch syndrome allows for interventions that can significantly reduce the development of cancer and improve survival. Targeted capture assays employing NGS technology allow for testing many genes simultaneously, including genes that would not necessarily have been tested using the phenotype-directed approach, as well as genes of less clearly established clinical utility” (Robson et al., 2015).According to ASCO, multi-gene panel testing is particularly useful in situations where there are multiple high-penetrance genes associated with a specific cancer, and “one example of such a situation is Lynch syndrome, when the results of immunohistochemical analysis are not available to direct testing”(Robson et al., 2015). 

U.S. Multi-Society Task Force on Colorectal Cancer 
In 2014, The U.S. Multi-Society Task Force on Colorectal Cancer (Giardiello et al., 2014):

Testing for MMR deficiency of newly diagnosed CRC should be performed. This can be done for all CRCs, or CRC diagnosed at age 70 years or younger, and in individuals older than 70 years who have a family historyconcerning for LS. Analysis can be done by IHC testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for MSI. Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis of MLH1 promoter hypermethylation.” Also, “Individuals who have a personal history of a tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation); uterine cancer diagnosed at younger than age 50 years; a known family MMR gene mutation; fulfill Amsterdam criteria or revised Bethesda guidelines; and/or have a personal risk of ≥5% chance of LS based on prediction models should undergo genetic evaluation for LS.” 

ASCP, CAP, AMP, and ASCO
American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and American Society of Clinical Oncology (ASCO) issued guidelines in 2017 stating “BRAF p.V600 mutational analysis should be performed in deficient MMR tumors with loss of MLH1 to evaluate for Lynch Syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome”. In addition, they have added the following recommendation for clinicians: “clinicians should order mismatch repair status testing in patients with colorectal cancers for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification” (Sepulveda et al., 2017). 

American College of Gastroenterology (ACG) 
In 2015, ACG issued the following practice guidelines for the management of patients with hereditary gastrointestinal cancer syndromes (Syngal et al., 2015): 

  • “All newly diagnosed colorectal cancers should be evaluated for mismatch repair deficiency.
  • 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.
  • 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.” 

American Society of Colon and Rectal Surgeons 
The American Society of Colon and Rectal Surgeons (Herzig et al., 2017) published guidelines which recommend (based on 2014 U.S. Multi-Society Task Force on Colorectal Cancer): 

“Universal testing (tumor testing)

  • Testing for MMR deficiency of newly diagnosed CRC should be performed
  • This can be done for all CRCs or CRC diagnosed at age ≤70 y and in individuals >70 y who have a family history concerning for LS
  • Analysis can be done by IHC testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for MSI
  • Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis of MLH1 promoter hypermethylation
  • To facilitate surgical planning, tumor testing on suspected CRC should be performed on preoperative biopsy specimens, if possible 

Traditional testing (germline testing)

  • Individuals who have a personal history of a Lynch syndrome–related tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation)
  • Personal history of uterine cancer diagnosed at age <50 y
  • A known family MMR gene mutation
  • Fulfill Amsterdam criteria or revised Bethesda guidelines

Have a personal risk of ≥5% chance of LS based on prediction models” 

References 

  1. Barrow, P., Khan, M., Lalloo, F., Evans, D. G., & Hill, J. (2013). Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg, 100(13), 1719-1731. doi:10.1002/bjs.9316  
  2. Brosens, L. A., Offerhaus, G. J. A., & F, M. G. (2015). Hereditary Colorectal Cancer: Genetics and Screening. Surg Clin North Am, 95(5), 1067-1080. doi:10.1016/j.suc.2015.05.004
  3. Cohen, S. A., Laurino, M., Bowen, D. J., Upton, M. P., Pritchard, C., Hisama, F., . . . Grady, W. M. (2016). Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice. Cancer, 122(3), 393-401. doi:10.1002/cncr.29758
  4. EGAPP. (2009). Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med, 11(1), 35-41. doi:10.1097/GIM.0b013e31818fa2ff
  5. Giardiello, F. M., Allen, J. I., Axilbund, J. E., Boland, C. R., Burke, C. A., Burt, R. W., . . . Rex, D. K. (2014a). Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc, 80(2), 197-220. doi:10.1016/j.gie.2014.06.006
  6. Giardiello, F. M., Allen, J. I., Axilbund, J. E., Boland, C. R., Burke, C. A., Burt, R. W., . . . Rex, D. K. (2014b). Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology, 147(2), 502-526. doi:10.1053/j.gastro.2014.04.001
  7. Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., . . . de la Chapelle, A. (2005). Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med, 352(18), 1851-1860. doi:10.1056/NEJMoa043146
  8. Hunter, J. E., Zepp, J. M., Gilmore, M. J., Davis, J. V., Esterberg, E. J., Muessig, K. R., . . . Goddard, K. A. (2015). Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers. Cancer, 121(18), 3281-3289. doi:10.1002/cncr.29470
  9. Jansen, M., Menko, F. H., Brosens, L. A., Giardiello, F. M., & Offerhaus, G. J. (2014). Establishing a clinical and molecular diagnosis for hereditary colorectal cancer syndromes: Present tense, future perfect? Gastrointest Endosc, 80(6), 1145-1155. doi:10.1016/j.gie.2014.07.049
  10. Kidambi, T. D., Blanco, A., Myers, M., Conrad, P., Loranger, K., & Terdiman, J. P. (2015). Selective Versus Universal Screening for Lynch Syndrome: A Six-Year Clinical Experience. Dig Dis Sci, 60(8), 2463-2469. doi:10.1007/s10620-014-3234-z
  11. Ligtenberg, M. J., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., . . . Hoogerbrugge, N. (2009). Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet, 41(1), 112-117. doi:10.1038/ng.283  
  12. Lynch, H. T., Lynch, P. M., Lanspa, S. J., Snyder, C. L., Lynch, J. F., & Boland, C. R. (2009). Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet, 76(1), 1-18. doi:10.1111/j.1399-0004.2009.01230.x
  13. Moreira, L., Balaguer, F., Lindor, N., de la Chapelle, A., Hampel, H., Aaltonen, L. A., . . . Castells, A. (2012). Identification of Lynch syndrome among patients with colorectal cancer. Jama, 308(15), 1555-1565. doi:10.1001/jama.2012.13088
  14. Peltomäki PT, O. G., Vasen HFA. (2010). Lynch syndrome. In C. F. Bosman FT, Hruban RH, Theise ND (Ed.), WHO Classification of Tumours of the Digestive System (4th ed., Vol. 3). Lyon: IARC Press.
  15. Provenzale, D., Gupta, S., Ahnen, D. J., Bray, T., Cannon, J. A., Cooper, G., . . . Darlow, S. (2016). Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 14(8), 1010-1030.
  16. Robson, M. E., Bradbury, A. R., Arun, B., Domchek, S. M., Ford, J. M., Hampel, H. L., . . . Lindor, N. M. (2015). American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 33(31), 3660-3667. doi:10.1200/jco.2015.63.0996
  17. Robson, M. E., Storm, C. D., Weitzel, J., Wollins, D. S., & Offit, K. (2010). American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol, 28(5), 893-901. doi:10.1200/jco.2009.27.0660
  18. Rumilla, K., Schowalter, K. V., Lindor, N. M., Thomas, B. C., Mensink, K. A., Gallinger, S., . . . Thibodeau, S. N. (2011). Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn, 13(1), 93-99. doi:10.1016/j.jmoldx.2010.11.011
  19. Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., . . . Nowak, J. A. (2017). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn, 19(2), 187-225. doi:10.1016/j.jmoldx.2016.11.001
  20. Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L., & Burt, R. W. (2015). ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110(2), 223-262; quiz 263. doi:10.1038/ajg.2014.435
  21. Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Ruschoff, J., . . . Srivastava, S. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst, 96(4), 261-268.
  22. Vasen, H. F., Mecklin, J. P., Khan, P. M., & Lynch, H. T. (1991). The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC).Dis Colon Rectum, 34(5), 424-425.  
  23. Vasen, H. F., Watson, P., Mecklin, J. P., & Lynch, H. T. (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. In Gastroenterology (Vol. 116, pp. 1453-1456). United States.
  24. Win, A. K., Parry, S., Parry, B., Kalady, M. F., Macrae, F. A., Ahnen, D. J., . . . Jenkins, M. A. (2013). Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol, 20(6), 1829-1836. doi:10.1245/s10434-012-2858-5  

Coding Section

Code Number

Description

  81288  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis 
  81292  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 
  81293  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants 
  81294  MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants 
  81295  MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 
  81296  MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants 
  81297  MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants 
  81298  MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 
  81299  MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants 
  81300  MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants 
  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 non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 
  81318 PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants 
  81319  PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
  81403

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

(Policy specific gene: EPCAM
  88341 Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)
  88342 Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure  
  88344 Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure 
  96040  Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family 
  S0265 Genetic counseling, under physician supervision, each 15 minutes
ICD-10-CM   C16.0-C16.9  Malignant neoplasm of stomach 
  C17-C17.9 Malignant neoplasm of small intestine
  C18.0-C18.9 Malignant neoplasm, colon
  C240.0-C24.9 Malignant neoplasm of other and unspecified parts of biliary tract
  C25.0-C25.9 Malignant neoplasm of pancreas
  C44.131 - C44.1392  Sebaceous cell carcinoma of skin of eyelid 
  C54.0 - C54.9   Malignant neoplasm of corpus uteri 
  C56.1 - C56.9  Malignant neoplasm of ovary 
  C65.1-C65.9 Malignant neoplasm of renal pelvis
  C66.1-C66.9 Malignant neoplasm of the ureter
  C67.0 - C67.9  Malignant neoplasm of bladder 
  C71.0 - C71.9  Malignant neoplasm of brain 
  D23.0 - D23.9  Other benign neoplasms of skin 
  L85.8 Other specified epidermal thickening
  Z15.04 Genetic susceptibility to malignant neoplasm of endometrium
  Z15.09 Genetic susceptibility to other malignant neoplasm
  Z80.41  Family history of malignant neoplasm of ovary 
  Z80.51 - Z80.59  Family history of malignant neoplasm of urinary tract 
  Z80.8  Family history of malignant neoplasm of other organs or systems 
  Z85.00  Personal history of malignant neoplasm of unspecified digestive organ 
  Z85.038  Personal history of other malignant neoplasm of large intestine 
  Z85.048  Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus 
  Z85.42  Personal history of malignant neoplasm of other parts of uterus 
  Z85.43  Personal history of malignant neoplasm of ovary 
  Z85.53  Personal history of malignant neoplasm of renal pelvis 
  Z85.54  Personal history of malignant neoplasm of ureter 
  Z85.59  Personal history of malignant neoplasm of other urinary tract organ 
  Z85.841  Personal history of malignant neoplasm of brain 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2017 Forward     

04/02/2019 

Annual review, major revision of policy for clarity and specificity of coding and testing criteria. Also adding rationale, regulatory status and updating coding. 

07/26/2018 

Annual review, rewriting medical necessity criteria to address the genes being tested in one medical necessity statement rather than breaking them out individually. Removing age criteria for testing. Updating guidelines to reflect the changes in the policy criteria. 

04/19/2018 

Interim review, month of review changed, no other changes 

08/03/2017 

Interim review clarifying medical necessity statement related to patients with 1 or more first degree relatives. Updating guidelines. 

05/01/2017

New Policy 


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