Up to one third of colorectal cancer (CRC) has a hereditary component, but only 5% to 10% are due to one of the high-risk, inherited cancer predisposition syndromes. Familial adenomatous polyposis (FAP) is an autosomal dominant CRC syndrome caused by variants in the adenomatous polyposis coli (APC) gene. However, some 20% to 40% of patients suspected of having FAP test negative for APC gene variants, and a proportion of these patients are subsequently diagnosed with MYHassociated polyposis (MAP). MAP is an autosomal recessive disorder caused by variants in the MYH (MUTYH) gene, located on chromosome 1 at band p32.1 to p34.4. MYH encodes a DNA glycosylase that functions in base excision repair following oxidative DNA damage. The presence of biallelic MYH variants (variants in both copies of the gene) leads to a hypermutability of APC and other genes involved in CRC development. As a result, MAP patients may develop colorectal polyposis and have a high risk of developing CRC. In addition, MAP patients may develop polyps or
tumors in other parts of the gastrointestinal tract, especially the duodenum, and may exhibit other features commonly seen in FAP (such as congenital hypertrophy of the retinal pigment epithelium [CHRPE]). The average age at onset for MAP patients is typically later than in FAP patients, often in the fifth decade of life. Both allele frequencies and the incidence of MAP vary depending on population background. In general, the 2 most common MYH gene variants are p.Tyr165Cys and p.Gly382Asp, which account for approximately 75% of all MYH gene alterations reported to date. The frequency of heterozygous MYH carriers in the general population is approximately 1% to 2%.