Molecular and clinical characteristics of MSH6 variants: An analysis of 25index carriers of a germline variant

The MSH6 gene is one of the mismatch-repair genes involved in hereditary no npolyposis colorectal cancer (HNPCC). Three hundred sixteen individuals who were known or suspected to have HNPCC were analyzed for MSH6 germline muta tions. For 25 index patients and 8 relatives with MSH6 variants, molecular and clinical features are described. For analysis of microsatellite instabi lity (MSI), the five consensus markers were used. Immunohistochemical analy sis of the MLH1, MSH2, and MSH6 proteins was performed. Five truncating MSH 6 mutations, of which one was detected seven times, were found in 12 index patients, and 10 MSH6 variants with unknown pathogenicity were found in 13 index patients. Fourteen (54%) of 26 colorectal cancers (CRCs) and endometr ial cancers showed no, or only weak, MSI. Twelve of 18 tumors of truncating -mutation carriers and 3 of 17 tumors of missense-mutation carriers showed loss of MSH6 staining. Six of the families that we studied fulfilled the or iginal Amsterdam criteria; most families with MSH6, however, were only susp ected to have HNPCC. In families that did not fulfill the revised Amsterdam criteria, the prevalence of MSH6 variants is about the same as the prevale nce of those in MLH1/MSH2. Endometrial cancer and/or atypical hyperplasia w ere diagnosed in 8 of 12 female carriers of MSH6 truncating mutations. Most CRCs were localized distally in the colon. Although, molecularly, missense variants are labeled as doubtfully pathogenic, clinical data disclose a gr eat resemblance between missense-variant carriers and truncating-mutation c arriers. We conclude that, in all patients suspected to have HNPCC, MSH6-mu tation analysis should be considered. Neither MSI nor immunohistochemistry should be a definitive selection criterion for MSH6-mutation analysis.