Cancer risks for MSH6 pathogenic variant carriers

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome caused by pathogenic variants (PVs) in DNA mismatch repair genes, including MSH6 . Although MSH6 -associated LS (MSH6 -LS) is known to increase the risk of several cancers, precise risk estimates—particularly for non-colorectal cancers—remain uncertain. This limits personalised clinical guidance for MSH6 -LS. This study aims to refine cancer risk estimates for individuals with pathogenic or likely pathogenic MSH6 variants. Methods A retrospective cohort study was conducted using data from 360 Dutch families, comprising 1117 MSH6 PV carriers identified between 1995 and 2020. Pedigree data were collected from multiple clinical centres. Cancer diagnoses were confirmed through medical records where available. Age- and sex-specific hazard ratios (HRs) and cumulative risks (CRs) were calculated using segregation analysis, adjusted for ascertainment bias. Results By age 80, the cumulative CRC risk was 36 % for males (95 % CI: 25–48 %) and 21 % for females (95 % CI: 13–32 %). For endometrial cancer, the CR was 23 % in females (95 % CI: 15–43 %). At age 40, CRC risk remained low: 0.2 % in males and 0.9 % in females. Elevated lifetime risks were observed for ovarian cancer (6.4 %; HR 5.58), urinary tract cancers (10.1 % in males, 4.1 % in females; HR 2.52), and biliary tract cancers (4.9 % in males, 4.2 % in females; HR 2.76). No increased risk was found for prostate or breast cancer. Conclusion These refined, age- and sex-specific risk estimates for MSH6 PV carriers inform tailored surveillance strategies, supporting delayed CRC screening and individualised counselling on risk-reducing surgery for women.