MUTYH Gene Mutation Analysis

MUTYH-Associated Polyposis

MUTYH-associated polyposis (MAP) (OMIM #608456) is an autosomal recessive disorder characterized by multiple colorectal adenomas and carcinomas. Individuals with MAP have an extremely high risk of developing colorectal cancer. MAP is caused by biallelic germline mutations in the mutY homolog (MUTYH) gene.1,2,4 The mean age of colorectal cancer diagnosis in untreated individuals is 45 years, several years later than in APC-related familial adenomatous polyposis (FAP).9 The phenotype is often undistinguishable from that of autosomal dominant FAP or attenuated FAP (AFAP) caused by mutations in adenomatous polyposis coli (APC) gene. The number of polyps in MAP patients is usually between 10 and 100, and affected individuals are often sporadic cases. However, biallelic MUTYH mutations have also been detected in patients affected with early-onset colorectal cancer without polyps and in one with more than 1000 polyps.7,8 The two most common mutations in Caucasians, accounting for about 75%-80% of mutant alleles, are Y165C (or Tyr165Cys) and G382D (or Gly382Asp).5 Prevalence of MUTYH mutations in other ethnic groups is currently unknown. The exact risk of colorectal cancer associated with monoallelic MUTYH mutation carriers remains uncertain; most large studies have described an odds ratio of <1.5.6

MUTYH gene is located on the short arm of chromosome 1 between positions 34.3 and 32.1.3 MUTYH is frequently also termed MYH. MUTYH is part of the Base Excision System which is responsible for the repair of oxidative DNA damage. Since 2002, biallelic germline mutations in the MUTYH gene were found to result in the accumulation of G:C→T:A transversion mutations in genes such as APC and KRAS, both of which have major roles in colorectal tumorigenesis1.

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MUTYH Gene Mutation Analysis Assay Summary
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  1. Al-Tassan N et al. Nat Genet. 2002 Feb;30(2):227-32
  2. Jones S et al. Hum Mol Genet. 2002 Nov 1;11(23):2961-7
  3. Cheadle JP et al. Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R159-65.
  4. Sieber OM et al. N Engl J Med. 2003 Feb 27;348(9):791-9.
  5. Gismondi V et al. Int J Cancer. 2004 May 1;109(5):680-4.
  6. Peterlongo P et al. Carcinogenesis. 2006 Nov;27(11):2243-9.
  7. Croitoru ME et al. J Natl Cancer Inst. 2004;96:1631–4.
  8. Isidro G et al. Hum Mutat. 2004;24:353–4.
  9. Nielsen M et al. J Med Genet. 2005 Sep;42(9):e54.