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Clinical Policy Title: COLARIS® testing for Lynch syndrome

Clinical Policy Number: CCP.1097

Effective Date: October 1, 2014

Initial Review Date: March 19, 2014

Most Recent Review Date: March 5, 2019

Next Review Date: March 2020

Related policies:

CCP.1050 Familial polyposis gene testing

CCP.1319 Colorectal cancer screening

ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas’ clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of “medically necessary,” and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas’ clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas’ clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas’ clinical policies are not guarantees of payment.

Coverage policy

AmeriHealth Caritas considers the use of COLARIS® testing, also known as genetic testing for the germline

mutations MLH1, MSH2, or MSH6, which causes hereditary nonpolyposis colorectal cancer, or Lynch

syndrome, to be clinically proven and, therefore, medically necessary in members who meet the following

criteria (Barrow, 2013; Boland, 2010; Bonis, 2007; Coates, 2011; Evaluation of Genomic Applications in

Practice and Prevention Working Group, 2009; Hampel, 2014; Palomaki, 2009; U.S. Multi-Service Task Force

on Colon Cancer, 2014):

The initial screening for Lynch syndrome to evaluate tissue tumor must use microsatellite instability or

immunohistochemistry with or without BRAF/MLH1 promoter methylation testing.

Those who are candidates for COLARIS® testing include:

Members with colorectal cancer diagnosed in the past.

Policy contains:

COLARIS® testing.

Colorectal cancer.

Lynch syndrome.

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Members with at-risk relatives diagnosed with Lynch syndrome with a known mismatch repair

mechanism mutation.

Members with endometrial cancer and one first-degree relative diagnosed with a Lynch-

associated cancer, with one of the cancers being diagnosed before age 50 for the diagnosis of

Lynch syndrome.

Members who have been diagnosed, before age 60, with colorectal cancer or endometrial

cancer and a high microsatellite instability in the tumor.

Members with a differential diagnosis of attenuated familial adenomatous polyposis versus

(mutY homolog) s (MUTYH-) associated polyposis versus Lynch syndrome.

Members without colorectal cancer but with a family history meeting the Amsterdam or

revised Bethesda criteria, when no affected family members have been tested for mismatch

repair mutations; members referred for genetic testing if family member meets Amsterdam II

or revised Bethesda criteria.

a. Amsterdam II clinical criteria (all criteria must be fulfilled) for defining families at high

risk for Lynch syndrome:

– Three or more relatives with a histologically verified hereditary nonpolyposis -

associated cancer (colorectal cancer or cancer of the endometrium, small intestine,

ureter, or renal pelvis), one of whom is a first-degree relative of the other two.

– Hereditary nonpolyposis-associated cancer involving at least two generations.*

– Cancer in one or more affected relatives diagnosed before age 50.

– Familial adenomatous polyposis excluded in any cases of colorectal cancer.

– Tumors should be verified by pathologic examination. (Note: Recognizing the

difficulty of obtaining pathology reports of family members, pathology reports

should be verified whenever possible.)

*Modifications allow for small hereditary nonpolyposis colorectal cancer families: Either these families

must have two colorectal cancers in first-degree relatives involving at least two generations, with at least

one individual diagnosed by age 55, or, in families with two first-degree relatives affected by colorectal

cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is

sufficient.

b. Revised Bethesda guidelines: Meeting any of the following is sufficient for consideration

of microsatellite instability/immunohistochemistry testing:

– Colorectal cancer diagnosed before age 50.

– Presence of synchronous or metachronous colorectal cancer or other Lynch-

associated tumor, regardless of age.

– Colorectal cancer with MSI-H histology diagnosed in an individual who is under age

60.

– Colorectal cancer diagnosed with one or more first-degree relatives with a Lynch-

related tumor, with one of the cancers diagnosed before age 50.

– Colorectal cancer diagnosed in two or more first- or second-degree relatives with a

Lynch-related tumor, regardless of age.

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– There has been a recommendation for testing made after genetic counseling

performed by a specialist or other physician equivalent to that provided by a genetic

counselor and also be appropriate for the test being requested.

*Note: Family history should include information on cancers in first-degree (parents, siblings, children) and

second-degree (grandparents, aunts/uncles, nieces/nephews, grandchildren) relatives on maternal and

paternal sides, including cancer type and age of person when diagnosed.

Limitations:

All other uses of COLARIS testing, also known as genetic testing for Lynch syndrome, are not clinically

proven and, therefore not medically necessary.

Testing must be performed at a participating laboratory facility when available.

Alternative covered services:

Colonoscopy for colorectal screening.

Network provider evaluation and surveillance.

Background

Colorectal cancer is the second most deadly cancer (behind only lung/bronchus cancer) of men and women

in the United States (Noone, 2018). In 2018, an estimated 140,250 Americans will be diagnosed with the

disease, and 50,260 will die from it (National Cancer Institute, 2018). Both diagnosis and death rates are

highest among African Americans. When colorectal cancer is detected early, illness and death can be

prevented. The U.S. Department of Health and Human Services is committed to boosting public awareness

about the importance of screening and treatment for colorectal cancer.

Colorectal cancer poses elevated risk to adults over age 50, and the United States Preventive Services Task

Force (2016) recommends that all individuals ages 50 to 75 be screened for colorectal cancer as part of

routine preventive health care. Currently, about one in three adults between the ages of 50 and 75 are not

receiving recommended screening (Centers for Disease Control and Prevention, 2013).

Lynch syndrome is an autosomal dominant familial cancer syndrome caused by mutations in multiple

susceptibility genes (e.g., MLH1, MSH2, MSH6, PMS2, EPCAM) and is associated with an increased lifetime

risk for colorectal cancer and other malignancies within the tumor spectrum including at least endometrial,

ovarian, gastric, small bowel, urothelial, hepatobiliary tract, sebaceous, and pancreatic cancers. Lynch

syndrome prevalence in colorectal cancer and endometrial cancer is estimated at 1 percent to 3 percent,

and annual incidence ranges between 1 of 660 and 1 of 2,000 (de la Chapelle, 2005). In individuals with

Lynch syndrome, the lifetime risk of colorectal cancer may be as high as 80 percent (Cancer.Net, 2017).

While the incidence of adenomas in individuals with Lynch syndrome is similar to that in the general

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population, the high rate of colorectal cancer is due to an acceleration of the adenoma to carcinoma

sequence.

Cancer risks associated with Lynch syndrome are largely derived from family studies. Mutations in MLH1

and MSH2 account for 70 percent to 90 percent of families with Lynch syndrome. The risk of colon and

endometrial cancer is lower in MSH6 and PMS2 mutation carriers, although the cancer risk may not be

lower for MSH6 carriers if data are extended to age 80. While individuals with a single MLH1, MSH2, MSH6,

and PMS2 mutation develop cancers in midlife, individuals with biallelic MLH1, MSH2, MSH6, and PMS2

mutations have a distinctive phenotype and tumor spectrum, and often develop cancer as early as the first

decade of life.

First-degree relatives of mutation carriers have a 50 percent probability of having the same germline

mutation. Despite the high penetrance of colorectal cancer and endometrial cancer and recommendations

of consideration for screening unaffected first-degree relatives following diagnosis of Lynch syndrome

proband, testing of genetic carriers who are unaffected with a Lynch-related cancer is not a Medicare

benefit and is statutorily excluded from coverage.

COLARIS is a genetic test that assesses a person’s risk of developing hereditary colorectal cancer and a

woman’s risk of developing hereditary uterine cancer. COLARISPLUS detects disease-causing mutations in the

MLH1, MSH2, MSH6, PMS2, EPCAM, and MYH genes that are responsible for the majority of Lynch

syndrome and MYH-associated polyposis cases.

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is the most common of the

hereditary colon cancer syndromes and is believed to account for 3 percent to 5 percent of all colorectal

cancers (U.S. National Library of Medicine, 2017). COLARIS is a test for Lynch syndrome. Knowing the

results may help patients and their physicians take steps to prevent cancer before it has a chance to

develop.

MYH-associated polyposis is caused by mutations in the mutY homolog (MYH) gene. Individuals with MYH-

associated polyposis have mutations in both of their mutY homolog genes — one from each parent — often

referred to as "biallelic mutY homolog (MYH) mutations." Patients often have no family history of colorectal

cancer or polyps in parents, although siblings may be affected. The mutY homolog gene is an important part

of the base excision repair pathway, which allows for repair of deoxyribonucleic acid mutations caused by

oxidative damage to cells.

COLARIS is a simple blood test or oral rinse sample used to find out if a patient has MLH1, MSH2, MSH6,

PMS2, EPCAM, or mutY homolog mutations. Knowing the results may help patients and their physicians act

before cancer has a chance to develop.

Searches

AmeriHealth Caritas searched PubMed and the databases of:

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UK National Health Services Centre for Reviews and Dissemination.

Agency for Healthcare Research and Quality Guideline Clearinghouse and evidence-based

practice centers.

The Centers for Medicare & Medicaid Services.

We conducted searches on January 17, 2019. Search terms were: “Colorectal Cancer,” “Gene testing,” and

“Lynch Syndrome.”

We included:

Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and

greater precision of effect estimation than in smaller primary studies. Systematic reviews use

predetermined transparent methods to minimize bias, effectively treating the review as a

scientific endeavor, and are thus rated highest in evidence-grading hierarchies.

Guidelines based on systematic reviews.

Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple

cost studies), reporting both costs and outcomes — sometimes referred to as efficiency studies

— which also rank near the top of evidence hierarchies.

Findings

Various professional societies and groups have endorsed universal genetic testing for Lynch syndrome for

all persons diagnosed with colorectal cancer. An early analysis conducted for the Agency for Healthcare

Research and Quality of 104 studies screening colorectal cancer patients included 40 studies assessed for

clinical validity; presence of age <50 years; history of colorectal cancer or endometrial cancer in a first-

degree relative; or multiple colorectal or endometrial cancers. Immunohistochemistry or microsatellite

instability testing of tumor tissue were each as effective as more complex tests. In the 61 other studies, no

long-term harm of testing was found, while genetic counseling was efficacious (Bonis, 2007).

The Evaluation of Genomic Applications in Practice and Prevention Working Group, an independent panel

of experts established by the Centers for Disease Control and Prevention, recommended genetic testing for

Lynch syndrome in all newly diagnosed colorectal cancer patients, but failed to find a specific genetic

testing strategy (Evaluation of Genomic Applications in Practice and Prevention, 2009; Palomaki, 2009).

A 2010 workshop in Jerusalem recommended that all colorectal cancer patients under age 70 should be

screened with immunohistochemistry or microsatellite instability for mismatch repair proteins. Any

abnormality means patients should be offered genetic counseling plus genetic testing for Lynch syndrome.

Patients with Lynch syndrome should receive an annual colonoscopy (Boland, 2010).

The U.S. Multi-Society Task Force on Colorectal Cancer, which consists of the American Society for

Gastroendoscopy, American Gastroenterological Association, American College of Gastroenterology, and

the American Society of Colon and Rectal Surgeons, recommended (2014) universal testing for Lynch

syndrome in all newly diagnosed colorectal cancer patients in persons under age 70 and persons over age

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70 with a family history of the syndrome. Testing can be done by immunohistochemistry and/or

microsatellite instability. In addition, the panel recommends genetic evaluation for Lynch syndrome for

persons with a history of a tumor with mismatch repair deficiency; with uterine cancer diagnosed by age

50; with a known family gene mutation; or with fulfillment of the Amsterdam criteria or Bethesda

guidelines.

Preliminary screening tests for colorectal cancer patients, including microsatellite instability,

immunohistochemistry, and BRAF and/or MLH1 promoter hypermethylation testing for cases with no

immunohistochemistry staining for MLH1, is recommended (Coates, 2011). This approach is expected to

improve efficiency and reduce costs in patients most likely to have mismatch repair mutations.

The National Comprehensive Care Network updated its recommendations for universal screening for for

Lynch syndrome among colorectal cancer patients, preferring immunohistochemistry or microsatellite

instability alone for those with a personal or family history, and immunohistochemistry and microsatellite

instability together for routine testing (2018). The Centers for Disease Control and Prevention in their

publication Healthy People 2020 includes a goal to increase the proportion of newly diagnosed colorectal

cancer patients tested for Lynch syndrome (U.S. DHHS, 2017).

A systematic review of 12 studies found that screening the general population for Lynch syndrome reduced

colorectal cancer incidence by 68 percent and all-cause mortality by 78 percent. Universal screening

beginning at age 20 resulted in the greatest gain, but was also not cost-effective. Authors concluded

inadequate evidence exists to compare harms and benefits for such screening (Prince, 2017).

Authors of a study of 1,344 colorectal cancer patients under age 60 recommended that microsatellite

instability be the initial test for population-based screening of Lynch syndrome in younger colorectal cancer

patients (Schofield, 2009). A meta-analysis of 1,114 Lynch syndrome families concluded 1 of 71 males and 1

of 102 females with MLH1 or MSH2 mutations can expect a diagnosis of colorectal cancer in the next five

years, and thus the standard for people in their 30s (colonoscopy every one to two years) might not be

justifiable for those in their 20s (Jenkins, 2015).

A systematic review of five studies of women with HNPCC failed 2to identify an evidence-based means for

surveilling members of families with Lynch syndrome mutations (Auranen, 2011). However, the

immunohistochemistry and microsatellite instability tests continue to be the standard for Lynch syndrome.

A study of 1,566 patients with colorectal cancer found 2.8 percent with Lynch syndrome (each had at least

three relatives with Lynch syndrome). It also found immunohistochemistry to be nearly as sensitive to as

microsatellite instability. Bethesda criteria failed to identify 28 percent of Lynch syndrome patients

(Hampel, 2008). Analyzing BRAF mutations can help in diagnosing Lynch syndrome; in one study of subjects

with at least one mismatch repair absent, BRAF mutation was found in 55 percent, or 36 of 65, simplifying

genetic testing for Lynch syndrome (Jin, 2013).

The Bethesda guidelines are helpful, but not in all cases. One study found 62 of 1,040 colorectal cancer

patients had an abnormal immunohistochemistry or microsatellite instability result, but 37 percent (23) of

these abnormalities did not meet Bethesda criteria (Canard, 2012). Another review found that tumor

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mismatch repair testing cases in persons under age 70 with colorectal cancer fulfilling Bethesda guidelines

missed 4.9 percent of Lynch syndrome cases, but required 28.6 percent fewer cases undergoing mutational

analysis than the universal approach (Moreira, 2012).

Detected mutations are often good predictors of colorectal cancer risk. One study found that carriers of the

EPCAM deletion had a 75 percent risk of colorectal cancer (Kempers, 2011), even though this deletion only

accounts for 1.1 to 2.8 percent of confirmed Lynch syndrome families (Kuiper, 2011). Conversely, in some

patient categories, testing for Lynch syndrome is not always effective. One study concluded that in

colorectal cancer patients under age 50 (“apparently sporadic”), only 21 percent have features of Lynch

syndrome (Goel, 2010).

While genetic testing patients and family members with colorectal cancer and other cancers is indicated,

there has been only one meta-analysis of efficacy, which found that nine of 10 studies described a

reduction of colorectal cancer incidence and mortality with registration and screening (Barrow, 2013).

Significant differences in the risk of developing cancer by age 70 were found between the mutations MH1,

MSH2, and MSH6. The risks of developing colorectal cancer were 41 percent for MLH1, 48 percent for

MLH2, and 12 percent for MSH6; for endometrial cancer, risks were 54, 21, and 16; and for ovarian cancer,

risks were 20, 24, and 1 percent (Bonadona, 2011).

Several cost-effectiveness analyses of testing for Lynch syndrome have been conducted. One study of

screening three to four relatives of persons diagnosed with colorectal cancer, using immunohistochemistry

and BRAF mutation testing, found a cost per life-year gained of $44,000 for testing up to 70 years, while

screening without an upper age limit cost $88,700 per life-year gained (Ladabaum, 2011). Testing women

with endometrial cancer who had at least one first-degree relative with a Lynch-associated cancer yielded a

favorable incremental cost-effectiveness ratio of $9,126 per life-year gained; testing all relatives of women

with endometrial cancer would be more costly, i.e., $648,494 per life-year gained (Kwon, 2011).

Policy updates:

In 2017, a total of 11 professional guidelines/other and 22 peer-reviewed references were added to this

policy.

In 2018, a total of one professional guideline and two peer-reviewed references were added to this policy.

In 2019, we added two professional guidelines/other to the policy. The policy ID changed from 02.01.10 to

CCP.1097.

References

Professional society guidelines/other:

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Boland CR, Shike M. Report from the Jerusalem workshop on Lynch syndrome – hereditary nonpolyposis

colorectal cancer. Gastroenterology. 2010;138(7):e2191-2197. Doi: 10.1053/j.gastro.2010.04.024.

Bonis PA, Trikalinos TA, Chung M, et al. Hereditary nonpolyposis colorectal cancer: diagnostic strategies and

their implications. Evid Rep Technol Assess (Full Rep). 2007;(150):1-180. PMC4781224.

Cancer.Net. Lynch Syndrome. May 2017. www.cancer.net/cancer-types/lynch-syndrome. Accessed January

19, 2018.

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. 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.

2009;11(1):35-41. Doi: 10.1097/GIM.0b013e31818fa2ff.

Giardello FM, Allen JI, Axibund JE, et al. Guideline on genetic evaluation and management of Lynch

syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer.

Gastrointestinal Endoscopy. 2014;80(2):197-220. Doi: 10.1038/ajg.2014.186.

Gulland, A. All patients with colorectal cancer should be tested for genetic condition, NICE advises BMJ

2017; 356 :j998. Doi: 10.1136/bmj.j998.

National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: colorectal

cancer. 2018. https://seer.cancer.gov/statfacts/html/colorect.html Accessed January 17, 2019.

National Comprehensive Cancer Network. Genetic/familial high-risk assessment: colorectal. Version 1.2018.

July 18, 2018. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed

January 17, 2019.

Noone AM, Howlader N, Krapcho M, et al. SEER cancer statistics review, 1975-2015, National Cancer

Institute. Bethesda, MD, Posted to the SEER web site, April 2018. https://seer.cancer.gov/csr/1975_2015/,

based on November 2017 SEER data submission. Accessed January 17, 2019.

Rubenstein JH, Enns R, Deidelbaugh J, Barkun A, Clinical Guidelines Committee. American

Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome.

Gastroenterology. 2015;149(3):777-782. Doi: 10.1053/j.gastro.2015.07.036.

U.S. Centers for Disease Control and Prevention (CDC). CRC screening rates remain low. Atlanta GA: CDC,

November 5, 2013. https://www.cdc.gov/media/releases/2013/p1105-colorectal-cancer-screening.html.

Accessed January 19, 2018.

U.S. Department of Health and Human Services. Healthy People 2020. Washington, D.C.: USDHHS Office of

Disease Prevention and Health Promotion. https://www.healthypeople.gov/2020/topics-

objectives/topic/genomics/objectives. Accessed January 19, 2018.

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U.S. Multi-Society Task Force on Colorectal Cancer. Guidelines on genetic evaluation and management of

Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. GIE

Journal. 2014:197–220. http://www.giejournal.org/article/S0016-5107(14)01839-2/pdf. Accessed January

19, 2018.

U.S. National Library of Medicine. Lynch syndrome. January 15, 2019.

https://ghr.nlm.nih.gov/condition/lynch-syndrome#statistics. Accessed January 17, 2019.

Peer-reviewed references:

Auranen A, Joutsiniemi T. A systematic review of gynecological cancer surveillance in women belonging to

hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand.

2011;90(5):437-444. Doi: 10.1111/j.1600-0412.2011.01091.x.

Barrow P, Khan M, Lalloo F, Evans DG, Hill J. 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. 2013;100(13):1719-1731. Doi: 10.1002/bjs.9316.

Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2,

and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22):2304-2310. Doi: 10.1001/jama.2011.743.

Bouzourene H, Hutter P, Losi L, et al. Selection of patients with germline MLH1 mutated Lynch syndrome by

determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9(2):167-172. Doi:

10.1007/s10689-009-9302-4.

Canard G, Lefevre JH, Colas C, et al. Screening for Lynch syndrome in colorectal cancer: are we doing

enough? Ann Surg Oncol. 2012;19(3):809-816. Doi: 10.1245/s10434-011-2014-7.

Capper D, Voigt A, Bozukova G, et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch

syndrome in MSI-H colorectal cancer. Int J Cancer. 2013;133(7):1624-1630. Doi: 10.1002/ijc.28183.

Coates R, Willliams M, Melilo S, Gudgeon J. Genetic testing for Lynch syndrome in individuals newly

diagnosed with colorectal cancer to reduce morbidity and mortality from colorectal cancer in their

relatives. PLoS Curr. 2011;3:RRN1246. Doi: 10.1371/currents.RRN1246.

de la Chapelle A. The incidence of Lynch syndrome. Familial Cancer. 2005;4(3):233-237. Doi:

10.1007/s10689-004-5811-3.

Goel A, Nagasaka T, Spiegel J, et al. Low frequency of Lynch syndrome among young patients with non-

familial colorectal cancer. Clin Gastroenterol Hepatol. 2010;8(11):966-971. Doi: 10.1016/j.cgh.2010.06.030.

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Grandval P, Baert-Desurmont S, Bonnet F, et al. Colon-specific phenotype in Lynch syndrome associated

with EPCAM deletion. Clin Genet. 2012;82(1):97-99. Doi: 10.1111/j.1399-0004.2011.01826.x.

Hampel H. NCCN increases the emphasis on genetic/familial high-risk assessment in colorectal cancer. J

Natl Comp Cancer Netw. 2014;12:829-831. Doi: 10.6004/jnccn.2014.0200.

Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with

colorectal cancer. J Clin Oncol. 2008;26(35):5783-5788. Doi: 10.1200/JCO.2008.17.5950.

Jenkins MA, Dowty JG, Ait Ouakrim D, et al. Short-term risk of colorectal cancer in individuals with Lynch

syndrome: a meta-analysis. J Clin Oncol. 2015;33(4):326-331. Doi: 10.1200/JCO.2014.55.8536.

Jin M, Hampel H, Zhou X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch

syndrome. Am J Pathol. 2013;140(2):177-183. Doi: 10.1309/AJCPB9FOVH1HGKFR.

Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM-positive

Lynch syndrome; a cohort study. Lancet Oncol. 2011;12(1):49-55. Doi: 10.1016/S1470-2045(10)70265-5.

Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in

Lynch syndrome. Hum Mutat. 2011;32(4):407-414. Doi: 10.1002/humu.21446.

Kwon JS, Scott JL, Gilks CB, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin

Oncol. 2011;29(16):2247-2252. Doi: 10.1200/JCO.2010.32.9979.

Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with

colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011;155:69-79. Doi: 10.7326/0003-4819-

155-2-201107190-00002.

Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal

cancer. JAMA. 2012;308(15):1555-1565. Doi: 10.1001/jama.2012.13088.

Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies

aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009;11(1):42-65. Doi:

10.1097/GIM.0b013e31818fa2db.

Prince AE, Cadigan RJ, Henderson GE, et al. Is there evidence that we should screen the general population

for Lynch syndrome with genetic testing? A systematic review. Pharmgenomics Pers Med. 2017;10:49-60.

Doi: 10.2147/PGPM.S123808.

Schofield L, Watson N, Grieu F, et al. Population-based detection of Lynch syndrome in young colorectal

cancer patients using microsatellite instability as the initial test. Int J Cancer. 2009;124(5):1097-1102. Doi:

10.1002/ijc.23863.

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Snowsill T, Coelho H, Huxley N, et al. Molecular testing for Lynch syndrome in people with colorectal

cancer: systematic reviews and economic evaluation. Health Technol Assess. 2017;21(51):1-238. Doi:

10.3310/hta21510.

Tognetto A, Michelazzo MB, Calabro GE, et al. A Systematic Review on the Existing Screening Pathways for

Lynch Syndrome Identification. Front Public Health. 2017;5:243. Doi: 10.3389/fpubh.2017.00243.

Centers for Medicare & Medicaid Services National Coverage Determinations:

No National Coverage Determinations identified as of the writing of this policy.

Under Medicare, genetic tests for cancer are a covered benefit only for a beneficiary with a personal history

of an illness, injury or signs and/or symptoms thereof (i.e., clinically affected). A person with a personal

history of a relevant cancer is a clinically affected person, even if the cancer is considered cured. Predictive

or presymptomatic genetic tests and services, in the absence of past or present illness in the beneficiary,

are not covered under national Medicare rules. CMS recognizes Lynch syndrome as “an autosomal

dominant syndrome that accounts for about 3 percent to 5 percent of colorectal cancer cases. [Lynch]

syndrome mutations occur in the following genes: hMLH1, hMSH2, hMSH6, PMS2 and EPCAM.” CMS also

recognizes FAP and MAP syndromes and their associated mutations.

Local Coverage Determinations:

L34912 Genetic testing for Lynch syndrome – First Coast Service Options, Inc.

L35349 MolDx: Genetic testing for Lynch syndrome – CGS Administrators LLC

L36370 MolDx: Genetic testing for Lynch syndrome – Noridian Healthcare Solutions LLC

L36374 MolDx: Genetic testing for Lynch syndrome – Noridian Healthcare Solutions LLC

L35024 MolDx: Genetic testing for Lynch syndrome – Palmetto GBA

L36793 MolDx: Genetic testing for Lynch syndrome – Wisconsin Physicians Service Insurance Corporation

Commonly submitted codes

Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not

an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill

accordingly.

CPT Code Description Comments

81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)

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 (muhtL homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

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CPT Code Description Comments

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) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81295 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (e.g., 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) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81298 MSH6 (mutS homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

81300 MSH6 (mutS homolog 6 [E. coli]) (e.g., 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]) (e.g., 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. cerevisae]) (hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

81403

Molecular pathology procedure, Level 4 (e.g., 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)

81435

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

ICD-10 Code Description Comments

C18.0 Malignant neoplasm of cecum

C18.1 Malignant neoplasm of appendix

C18.2 Malignant neoplasm of ascending colon

C18.3 Malignant neoplasm of hepatic flexure

C18.4 Malignant neoplasm of transverse colon

C18.5 Malignant neoplasm of splenic flexure

C18.6 Malignant neoplasm of descending colon

13

ICD-10 Code Description Comments

C18.7 Malignant neoplasm of sigmoid colon

C18.8 Malignant neoplasm of overlapping sites of colon

C18.9 Malignant neoplasm of colon, unspecified

C19 Malignant neoplasm of rectosigmoid junction

C54.1 Malignant neoplasm of endometrium

K63.5 Polyp of colon

Z80.0 Family history of malignant neoplasm of digestive organs

Z83.71 Family history of colonic polyps

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

Z86.010 Personal history of colonic polyps

HCPCS Level II Code

Description Comments

N/A