Unsolved problems deal with genotype–phenotype correlations, pathogenicity of unclassified variants, cross-talk between BER and other DNA repair pathways including MMR, overlapping between MAP and HNPCC syndromes, and last, but not least, tumor suppressor role of MUTYH in pre-cancerous cells subjected to oxidative stress. This evidence concerns the gene MUTYH and mutyh-associated polyposis.