A multilevel perspective on <scp> <i>MSH6</i> </scp> ‐associated Lynch syndrome: Integrating molecular, biological, and clinical insights

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by a germline pathogenic variant in one of the mismatch repair (MMR) genes. Among these, MSH6-associated LS represents a distinct subtype with unique molecular and clinical characteristics. Despite its relatively high prevalence (~1 in 758 individuals) compared with MLH1- (1 in 1946) and MSH2-associated LS (1 in 2841), MSH6-associated LS remains underrepresented in research and clinical guidelines. To bridge this knowledge gap, we reviewed current literature on molecular, biological, and clinical aspects of MSH6-associated LS. From a biological perspective, loss of MSH6 function results in a relatively low degree of microsatellite instability and potentially slower tumor progression compared with other LS subtypes. Nevertheless, tumor immunogenicity of MSH6-associated colorectal cancers appears preserved, supporting responsiveness to immune checkpoint inhibitors. Clinically, pathogenic MSH6 (path_MSH6) variant carriers have a unique tumor spectrum, characterized by a relatively lower colorectal cancer penetrance (~8.1%-44%) compared with path_MLH1 and path_MSH2 carriers, but a relatively high endometrial cancer risk (~16%-44%), with a median age of onset approximately a decade later than that observed for path_MLH1 or path_MSH2 carriers. Phenotypic heterogeneity among path_MSH6 carriers may reflect contributions from modifier genes, environmental exposures, microbiome composition and/or the individual's HLA type. Recognition of the distinct biology of MSH6-associated LS and its clinical implications highlights the importance of gene-specific precision in clinical care, such as initiating colonoscopy surveillance at a later age (30-35 years) and performing it every 2-3 years.