MSH2 and cancer: Cumulative risks of LS-associated cancers depend on sex and distribution of MMR gene pathogenic variants.2MLH1 and MSH2 pathogenic variants raise the lifetime risk of CRC to around 50%,37 while PMS2 variants raise the lifetime risk of CRC up to 12% and 13% for endometrial cancer.2 32 Given that PMS2 pathogenic variants are less frequent, we consider that a 40% CRC risk among relatives identified with LS through cascade testing is a realistic assumption, consistent with the German-based model (42% risk of CRC among LS cases by age 80 years) and with EGAAPP consensus.5 18 20