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MSH3 encodes a MutS homolog that forms the MutSβ heterodimer with MSH2 to recognize insertion/deletion loops during DNA mismatch repair (MMR). Lynch syndrome is most commonly caused by pathogenic variants in MLH1, MSH2, MSH6 and PMS2. Unlike these high-penetrance genes, MSH3 has not been definitively implicated as a primary monogenic cause of Lynch syndrome but may act as a low-risk modifier allele in some families. MSH3 and Lynch syndrome share a mechanistic link via defective MMR.
In a study of 79 unrelated Lynch patients negative for MLH1, MSH2 and MSH6 pathogenic variants, 13 MSH3 alleles (silent, missense, intronic) were identified. In one family, the index with early-onset colorectal carcinoma carried two germline MSH3 missense variants, c.2732T>G (p.Leu911Trp), co-segregating with disease alongside an MSH2 polymorphism, suggesting a contributory role for MSH3 in colorectal tumour progression (PMID:21128252).
Two Lynch syndrome patients were reported to harbour heterozygous germline truncating variants in both MSH3 (c.1035del and c.2732T>G) and MSH6, with additional somatic second hits abrogating all MSH2 binding partners. This observation implies that MSH3 defects alone are insufficient to cause Lynch syndrome but may aggravate MSH6-related phenotypes in affected relatives (PMID:28528517).
Overall segregation evidence is limited, with only one affected family showing clear co-segregation of MSH3 variants. No reports demonstrate multigenerational segregation of isolated MSH3 variants in Lynch syndrome pedigrees, and no recurrent pathogenic MSH3 variants have been conclusively linked to disease onset.
Functional assays in yeast and human cells confirm that MSH3 participates in MMR: the MSH2–MSH3 complex binds insertion/deletion loops and interacts with proliferating cell nuclear antigen (PCNA) to maintain genomic stability. However, no in vivo models replicate a Lynch syndrome–like phenotype from MSH3 loss alone, and MSH3 deficiency predominantly yields elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) rather than classic high-level microsatellite instability.
Together, genetic and experimental data support only a limited modifier role for MSH3 in Lynch syndrome. MSH3 testing is not routinely warranted in diagnostic germline panels for Lynch syndrome, but its variants may modulate disease severity in the context of other MMR gene defects. Key take-home: MSH3 functions in MMR but lacks sufficient primary evidence to be considered a monogenic Lynch syndrome gene, serving instead as a low-risk modifier in select families.
Gene–Disease AssociationLimitedMSH3 variants behave as low-risk alleles in one small family; no primary pathogenic MSH3 variants proven Genetic EvidenceLimitedOne Lynch family with co-segregation of MSH3 c.2732T>G; absence of multigenerational segregation and lack of recurrent pathogenic variants Functional EvidenceLimitedBiochemical and yeast assays confirm MSH3 in MMR but no in vivo model demonstrates Lynch syndrome phenotype from MSH3 loss alone |