MUTYH (mutY DNA glycosylase) is a base excision repair enzyme that removes inappropriately paired adenine bases opposite 8-oxoguanine lesions, preventing G:C to T:A transversions caused by oxidative DNA damage 1. The protein possesses both adenine and 2-OH-A DNA glycosylase activities and functions in the nucleoplasm and mitochondria as part of mismatch repair pathways 1. Biallelic MUTYH mutations cause MUTYH-associated polyposis (MAP), an autosomal recessive syndrome characterized by multiple colorectal adenomas and very high colorectal cancer risk, phenotypically similar to familial adenomatous polyposis 2. Monoallelic mutations confer increased colorectal cancer risk even without biallelic inheritance 3. Loss of functional MUTYH protein results in accumulation of G:T mismatches and characteristic mutational signatures in tumors 4. Beyond colorectal disease, germline MUTYH mutations increase risk for duodenal adenomas, gastric cancer, and pancreatic neuroendocrine tumors 5. Functional studies show missense variants exhibit variable complementation activity, with some variants severely impairing glycosylase activity while others retain near-normal function 6. MAP patients require specialized genetic counseling and lifelong surveillance protocols.