Furthermore, individuals with Lynch syndrome frequently develop MSI CRCs due to germline mutations in one of the MMR genes (MLH1, MSH2, MSH6, and PMS2); mutations in MLH1 or MSH2 gene lead to an increased risk (70–80%) of developing cancer, while mutations in the MSH6 or PMS2 gene have a comparatively lower risk (25–60%) of cancer development [111] On the contrary, sporadic MSI CRCs frequently display loss of MMR activity due to MLH1 silencing by aberrant DNA methylation [112,113]. This evidence concerns the gene MSH6 and cancer.