Mutations in mismatch repair genes, including MLH1, MSH2, MSH6, and PMS2, are implicated in the pathogenesis of the syndrome through microsatellite instability (MSI) and a rapid adenoma-carcinoma sequence.
Despite the increasing number of MSH6 germline mutations, their pathogenicity remains questionable, because the mutations are mainly linked to putative HNPCC families lacking the typical clinical and molecular characteristics of the syndrome, such as early age at onset and high microsatellite instability (MSI).