The exact role of MUTYH in CRC tumorgenesis is not fully determined, but a defective BER system due to germline MUTYH mutations leads to somatic mutations in the APC gene. Furthermore, cooperation between the BER and MMR systems exists, and possibly monoallelic defects in both pathways are of significance to CRC development. The two most common MUTYH variants, Y179C and G396D, both generate dysfunctional gene products, but Y179C has the most severe functional consequences and possibly causes a more severe phenotype.
Median clinical onset of MAP is 47 years of age, and due to the recessive mode of inheritance, most have already developed CRC. Typically MAP patients develop between 10-100 colorectal adenomas, although polyposis may not be obligatory for MAP. Typical FAP and HNPCC associated extracolonic manifestations are not common in MAP, except for upper gastro-duodenal polyposis which can be part of the phenotype, but more seldom than in FAP. Recommended MAP surveillance is colonoscopy with polypectomy from 20-25 years of age. In the future, genetic testing as well as surveillance may be targeted according to specific ethnic MUTYH mutation variants and genotype-phenotype correlations.