CAM 168

Familial Adenomatous Polyposis and MUYTH-Associated Polyposis Testing

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

Familial adenomatous polyposis (FAP) is characterized by development of adenomatous polyps and an increased risk of colorectal cancer (CRC) caused by an autosomal dominant mutation in the APC (Adenomatous Polyposis Coli) gene (Kinzler & Vogelstein, 1996). Depending on the location of the mutation in the APC gene, FAP can present as the more severe classic FAP (CFAP) with hundreds to thousands of polyps developing in the teenage years associated with a significantly increased risk of CRC, or attenuated FAP with fewer polyps, developing later in life and less risk of CRC (Brosens, Offerhaus, & F, 2015; Spirio et al., 1993).

MUTYH-associated polyposis (MAP) results from an autosomal recessive mutation of both alleles of the MUTYH gene (Nielsen, Morreau, Vasen & Hes, 2011) and is characterized by increased risk of CRC, but can present without development of adenomatous polyps.

Inherited syndromes that express adenomatous polyps and confer a significantly increased risk of CRC include Lynch syndrome, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) (Jasperson, Tuohy, Neklason & Burt, 2010). Lynch Syndrome is discussed in a separate policy (M2004).

Familial adenomatous polyposis (FAP) results from mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. The prevalence of FAP is about 1:13,000 (Brosens et al., 2015). More than 300 different mutations have been reported, with the clinical presentation dependent on the location of the mutation in the APC gene (Brosens et al., 2007; Spirio et al., 1993). Mutations in the central part of the gene result in classic FAP characterized by the presence of 100 or more adenomatous colorectal polyps (Jansen, Menko, Brosens, Giardiello & Offerhaus, 2014; Talley 2017). When fully developed, patients can have up to thousands of colorectal adenomas and have a 100 percent risk of colorectal cancer (CRC). About 50% of patients developed adenomas by age 15 and 95% by age 35. If left untreated, FAP patients will develop CRC at an average age of 39 (range 35-43 year) (Trimbath & Giardiello, 2002).

In contrast, mutations in either end of the gene predispose to AFAP (Spirio et al., 1993). An attenuated form of FAP is characterized by few colorectal adenomas with a later age of onset and an 80 percent lifetime risk of CRC. The diagnosis should be considered in patients 40-50 year old with 10-100 adenomas cumulatively. Patients with AFAP have a 70% lifetime risk of CRC, about 12 years later than in classic FAP (Jasperson et al., 2010; Trimbath & Giardiello, 2002).

Patients with FAP are also at risk for several extracolonic malignancies (Talley 2017).

MUTYH-associated polyposis is caused by biallelic mutations in the MUTYH gene base excision repair gene whose protein repairs oxidative damage to the DNA (Sieber et al., 2003). Failure of base excision repair results in transversions in multiple genes, including the APC and KRAS genes (S.S. Grover, Elena., 2017). More than 100 unique MUTYH gene mutations have been reported; however, the target genes that are mutated as a consequence of oxidative damage most strongly influence the polyposis phenotype (Boparai et al., 2008).

MUTYH-associated polyposis is usually characterized by development of between 10 to 100 colorectal polyps by the fifth or sixth decade (S. Grover et al., 2012; Sieber et al., 2003). However, MUTYH mutations have been identified in colorectal cancer (CRC) with few or no colorectal polyps (Balaguer et al., 2007; Wang et al., 2004). Adenomas are the predominant polyp type in patients with MUTYH-associated polyposis; however, multiple hyperplastic and/or sessile serrated polyps have been reported in some patients.

Guidelines have been established by several organizations to reduce morbidity and mortality from hereditary forms of polyposis and resulting colorectal cancer by identifying individuals at risk and implementing a highly targeted program of cancer surveillance and management guided by the causative mutations identified (Hampel, Bennett, Buchanan, Pearlman & Wiesner, 2015; Hegde, Ferber, Mao, Samowitz & Ganguly, 2014; Provenzale et al. 2016; Syngal et al. 2015).


  1. Genetic counseling is recommended for individuals being considered for genetic testing for FAP/AFAP and/or MAP.
  2. Complete sequencing of the APC gene considered MEDICALLY NECESSARY for:
    • Individuals with a personal history of >10  adenomatous colon polyps, or
    • Individuals with a personal history of a desmoid tumor, hepatoblastoma or cribriform-morular variant of papillary thyroid cancer, or multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE), or
    • Individuals with a family history of FAP, AFAP, or MAP, and the familial mutation is unknown
  3. Duplication/deletion analysis of the APC gene considered MEDICALLY NECESSARY when:
    • Sequencing of the APC gene does not reveal deleterious changes, and the clinical suspicion of FAP remains, or
    • There is a known familial duplication or deletion
  4. Testing for known familial mutations in the APC gene considered MEDICALLY NECESSARY for first degree relatives of an individual with known FAP.
  5. Testing for the two common MUTYH mutations (Y179C and G396D) is considered MEDICALLY NECESSARY when
    • There is a personal history of  >10  adenomatous colon polyps OR
    • APC gene testing is negative and high clinical suspicion for FAP/AFAP remains
    • The individual meets the following criteria for serrated polyposis syndrome (SPS) with at least some adenomas
      • At least 5 serrated polyps proximal to the sigmoid colon with 2 or more of these being greater than 10 mm; or
      • Greater than 20 serrated polyps of any size, but distributed throughout the colon.
      • Any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis
    • The two common mutations are known familial mutations
  6. Sequencing of the MUTYH gene considered MEDICALLY NECESSARY when
    • Testing for the two common mutations (Y179C and G396D) is negative, or only one common mutation is detected, and the clinical suspicion of MAP remains, OR
    • Testing is being requested in a member with a known familial mutation in MUTYH. This testing should be limited to the known familial mutation. 
  7. Sequencing of the MUTYH gene in children IS NOT MEDICALLY NECESSARY when one of the parents is unaffected and does not have MUTYH mutation and the other parent has MAP.
  8. Duplication/deletion analysis of the MUTYH gene considered MEDICALLY NECESSARY when
    • Sequencing of the MUTYH gene does not detect a mutation, and the clinical suspicion of MAP remains, OR
    • There is a known familial duplication or deletion
  9. Multi-gene testing is considered MEDICALLY NECESSARY in individuals who meet the APC and MUTYH testing criteria and have no known APC or biallelic mutations.  
  10. Multi gene testing IS NOT MEDICALLY NECESSARY in the following situations: an individual is from a family with a known mutation without any other reason for multi-gene testing OR multi-gene testing being used as a first line testing when the family history is strongly suggestive of a known hereditary  syndrome.
  11. If a pathogenic mutation has been identified in the index patient, predictive testing for the mutation considered MEDICALLY NECESSARY for the first-degree relatives. In typical FAP, family members that are found to carry the mutation is covered to undergo periodic examination of
    • the recto-sigmoid from the early teens, and
    • the upper gastrointestinal tract from age 25–30 years to monitor adenoma development. 

Policy Guidelines 
National Comprehensive Cancer Network (NCCN)
The NCCN recommends APC gene testing for individuals with a personal history of >10 adenomas, or with a personal history of a desmoid tumor, hepatoblastoma, cribriform-morular variant of papillary thyroid cancer or multifocal/bilateral, and for individuals with a known deleterious familial mutation (Provenzale et al., 2016). NCCN recommends MUTYH genetic testing for individuals with a personal history of >10 adenomas, known deleterious MUTYH mutations in family and for individuals meeting criteria for serrated polyposis syndrome with at least some adenomas (Provenzale et al., 2016).

When there is no known familial mutation, NCCN recommends comprehensive genetic testing, beginning with APC gene testing. If a mutation is not found in the APC gene, NCCN recommends that testing for the two common MUTYH mutations should be performed, and if biallelic mutations are not found, sequencing of the MUTYH gene should follow. When there are known familial mutations in either the APC or MUTYH genes, NCCN recommends testing for those mutations instead of full gene sequencing.

Siblings of individuals affected with MAP and children of individuals with MAP are recommended to have biallelic testing for the familial mutations. If one mutation is found, then sequencing of the entire gene is recommended. Also, sequencing of the MUTYH gene may be considered for the unaffected parent, and if that sequencing does not reveal any deleterious mutations, then the NCCN indicates that genetic testing of the children is not considered necessary.

The NCCN guidelines also mention that next generation sequencing technology allows for the sequencing of multiple genes associated with a specific family cancer phenotype or multiple phenotypes simultaneously. NCCN states: "examples of clinical scenarios for which multi-gene testing should be considered include adenomatous polyposis (APC, MUTYH, POLE, POLD1)." NCCN also states: "when more than one gene can explain an inherited cancer syndrome, multi-gene testing may be more efficient and cost-effective." NCCN recommends: "there is a role for multi-gene testing in individuals who have tested negative for a single syndrome, but whose personal and family history remains strongly suggestive of an inherited susceptibility." Due to several limitations and challenges associated with multi-gene testing, the NCCN panel recommends that: "when multi-gene testing is offered, it is done in the context of professional genetic expertise with pre- and post-test counseling being offered" (Provenzale et al., 2016).

American College of Gastroenterology (ACG)
The ACG recommends that: "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 (abdominal>peripheral), papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium ((CHRPE), 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" (Syngal et al., 2015).

ACG further states: "failure to identify a mutation in an index case does not rule out the diagnosis of adenomatous polyposis, as mutations cannot be found in all families. If testing is negative, and clinical suspicion remains high, testing for other possible underlying genes should be considered. Failure to find a mutation means that all close relatives must still be screened as if they have FAP. Finding a mutation confirms the diagnosis of adenomatous polyposis and allows relatives to be tested with a high degree of accuracy. Once an affected patient has been genotyped, all at-risk relatives can be screened for the mutation" (Syngal et al., 2015).

American College of Medical Genetics and Genomics (ACMG)
ACMG recommends testing for APC mutations in individuals with "10 or more polyps with autosomal dominant inheritance, and for at-risk family members of individuals with known familial mutations, and in individuals with congenital hypertrophy of retinal pigment epithelium, osteomas, supernumerary teeth, odontomas, desmoids, epidermoid cysts, duodenal and other small-bowel adenomas, gastric fundic gland polyp" (Hegde et al., 2014). It also recommended that: "FAP testing be performed using full sequencing of the APC gene. If no mutation is detected, then testing for large gene rearrangements should be performed" (Hegde et al., 2014).

ACMG recommends MUTYH gene testing for individuals with colorectal cancer diagnosed at less than 40 years of age, 10 – 100 adenomatous polyps in the absence of APC gene mutation and a family history of colon cancer consistent with an autosomal recessive inheritance (Hegde et al., 2014). ACMG indicates that MUTYH testing should begin with testing for the two common mutations, and if none or one mutation is identified, then sequencing of the MUTYH gene should be considered (Hegde et al., 2014). The ACMG also recommends that testing of the MUTYH gene should be offered to at-risk family members.

American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC)
ACMG and NSGC recommend that referral for genetic counseling should be considered for "any individual with a personal history of or first-degree relative with (i) a total of ≥ 10 adenomatous colon polyps with or without a colorectal or other FAP-associated cancer; (ii) a cribriform morular variant of papillary thyroid cancer; (iii) a desmoid tumor; or (iv) hepatoblastoma diagnosed before age 5" (Hampel et al., 2015).


  1. Balaguer, F., Castellvi-Bel, S., Castells, A., Andreu, M., Munoz, J., Gisbert, J. P., . . . Pique, J. M. (2007). Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol, 5(3), 379-387. doi:10.1016/j.cgh.2006.12.025
  2. Boparai, K. S., Dekker, E., Van Eeden, S., Polak, M. M., Bartelsman, J. F., Mathus-Vliegen, E. M., . . . van Noesel, C. J. (2008). Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology, 135(6), 2014-2018. doi:10.1053/j.gastro.2008.09.020
  3. 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
  4. Brosens, L. A., van Hattem, W. A., Jansen, M., de Leng, W. W., Giardiello, F. M., & Offerhaus, G. J. (2007). Gastrointestinal polyposis syndromes. Curr Mol Med, 7(1), 29-46.  
  5. Grover, S., Kastrinos, F., Steyerberg, E. W., Cook, E. F., Dewanwala, A., Burbidge, L. A., . . . Syngal, S. (2012). Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. Jama, 308(5), 485-492. doi:10.1001/jama.2012.8780
  6. Grover, S. S., Elena. (2017). MUTYH-associated polyposis - UpToDate. In J. Lamont (Ed.), UpToDate. Waltham. MA.
  7. Hampel, H., Bennett, R. L., Buchanan, A., Pearlman, R., & Wiesner, G. L. (2015). A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med, 17(1), 70-87. doi:10.1038/gim.2014.147
  8. Hegde, M., Ferber, M., Mao, R., Samowitz, W., & Ganguly, A. (2014). ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med, 16(1), 101-116. doi:10.1038/gim.2013.166
  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. Jasperson, K. W., Tuohy, T. M., Neklason, D. W., & Burt, R. W. (2010). Hereditary and Familial Colon Cancer. Gastroenterology, 138(6), 2044-2058. doi:10.1053/j.gastro.2010.01.054
  11. Kinzler, K. W., & Vogelstein, B. (1996). Lessons from hereditary colorectal cancer. Cell, 87(2), 159-170.
  12. Nielsen, M., Morreau, H., Vasen, H. F., & Hes, F. J. (2011). MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol, 79(1), 1-16. doi:10.1016/j.critrevonc.2010.05.011
  13. 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.
  14. Sieber, O. M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R. K., . . . Tomlinson, I. P. (2003). Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med, 348(9), 791-799. doi:10.1056/NEJMoa025283
  15. Spirio, L., Olschwang, S., Groden, J., Robertson, M., Samowitz, W., Joslyn, G., . . . et al. (1993). Alleles of the APC gene: an attenuated form of familial polyposis. Cell, 75(5), 951-957.
  16. 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
  17. Talley, N. (2017). Familial adenomatous polyposis: Screening and management of patients and families - UpToDate. In J. Lamont (Ed.), UptoDate. Waltham. MA.
  18. Trimbath, J. D., & Giardiello, F. M. (2002). Review article: genetic testing and counselling for hereditary colorectal cancer. Aliment Pharmacol Ther, 16(11), 1843-1857.
  19. Wang, L., Baudhuin, L. M., Boardman, L. A., Steenblock, K. J., Petersen, G. M., Halling, K. C., . . . Thibodeau, S. N. (2004). MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology, 127(1), 9-16.

Coding Section 

Code Number Description
CPT 81201 APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis (FAP), attenuated FAP) gene analysis; full gene sequence
APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis (FAP), attenuated FAP) gene analysis; known familial variants
  81203 APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis (FAP), attenuated FAP) gene analysis; duplication/deletion variants
  81401  Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat);MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D)
  81406  Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication /deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia when specified as the following:MUTYH (mutY homolog [E.coli]) (eg, MYH-associated polyposis), full gene sequence
  81435 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11
  81436 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11
ICD-10-CM  D12.0, D12.1, D12.2, D12.3, D12.4, D12.5, D12.6, K63.5 Colon polyps diagnoses
  Z86.010 Personal history of polyps
  D48.1 Desmoid tumor diagnosis
  Z87.39 Personal history of desmoid tumor
  Z83.71 Family history of colonic polyps
  Z84.89 Family history of other specified conditions
  Z15.89 Genetic susceptibility to disease

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     


Interim review. Genetic counseling is recommended is replacing Genetic counseling is Medically necessary. No other changes made


Annual review, no change to policy intent. 


Annual review, adding AFAP to genetic counseling criteria,updating criteria #5 to clarify serrated polyps and separating personal history of polyps from APC gene testing, adding statement about sequencing of MUTYH gene in children, adding statement regarding multi gene testing. No other changes made. 


New Policy

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