Phenotypic heterogeneity in carriers of a pathogenic MSH2 variant: implications for the diagnosis of Lynch syndrome.

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline pathogenic variants in mismatch repair (MMR) genes and is primarily associated with colorectal and endometrial cancers. Classically, Lynch syndrome-associated tumors exhibit microsatellite instability (MSI) and loss of MMR protein expression on immunohistochemistry (IHC); therefore, MSI and IHC are routinely used in screening algorithms to support diagnostic evaluation. ; Methods: In this study, we present the molecular and pathological characteristics of four cases from three unrelated families carrying the same MSH2 variant [c.70C > T (p.Gln24Ter)], interpreted as pathogenic, who were diagnosed with breast and colorectal cancer. MSI analysis and MMR protein expression were evaluated in available tumor tissues. ; Results: Preserved MMR protein expression was observed in three cases, and two cases were microsatellite stable (MSS), whereas only one case demonstrated loss of MMR protein expression and an MSI-high phenotype consistent with the classical Lynch syndrome profile. These findings suggest that individuals carrying the same MSH2 variant may exhibit heterogeneous tumor-level MMR/MSI phenotypes. Early truncating variants in MSH2 may allow partially functional protein production via alternative translation initiation, potentially limiting complete loss of MMR function. Variability in somatic second-hit mechanisms and tumor-specific molecular pathways may also contribute to this heterogeneity. ; Conclusion: In conclusion, Lynch syndrome tumor biology may be more heterogeneous than expected, and MSI and IHC should not be interpreted in isolation as exclusionary tests for an underlying germline MMR variant, but rather as markers of tumor-level biological consequences. Therefore, germline findings, tumor characteristics, and family history should be evaluated together in Lynch syndrome diagnosis and risk assessment.