MSH6 – Lynch syndrome

Lynch syndrome is an autosomal dominant cancer predisposition characterized by early-onset colorectal and extracolonic malignancies due to germline defects in DNA mismatch repair (MMR) genes. MSH6 (HGNC:7329) is one of four core MMR genes, and heterozygous loss‐of‐function variants in MSH6 confer moderate to high risks for colorectal, endometrial, and other tumors (MSH6; Lynch syndrome).

Clinical Validity: Definitive

The association between MSH6 and Lynch syndrome meets ClinGen Definitive criteria based on >100 unrelated probands with pathogenic MSH6 variants, demonstration of autosomal dominant inheritance with segregation in multiple families, and concordant tumor immunohistochemistry and microsatellite instability analyses. Functional assays uniformly show impaired MMR activity for pathogenic variants.

Genetic Evidence (Strong)

MSH6-associated Lynch syndrome exhibits autosomal dominant inheritance. Segregation has been documented in >19 affected relatives across multiple families carrying MSH6 pathogenic variants. Over 80 probands harbor frameshift and nonsense mutations (e.g., c.2194C>T (p.Arg732Ter) (PMID:31851094)), splice‐site alterations, and missense variants classified as pathogenic after functional testing. The variant spectrum includes at least 12 nonsense, 8 frameshift, >10 splice‐site, and numerous damaging missense changes, with recurrent Ashkenazi founder alleles (c.3984_3987dup (p.Leu1330ValfsTer12)) identified in 19 carriers (PMID:19851887).

Functional / Experimental Evidence (Strong)

Pathogenic MSH6 variants abrogate mismatch binding and ATPase‐coupled repair. In vitro assays of MSH6 nonsense and frameshift proteins show absent or severely reduced G·T and insertion/deletion mismatch recognition, confirmed by hypermutation in hprt and supFG1 reporters (PMID:9054582; PMID:8910404). Yeast models and biochemical reconstitution demonstrate dominant negative effects of select missense substitutions on Msh2–Msh6 heterodimer function, consistent with loss‐of‐function pathogenicity.

Conflicting Evidence

Several MSH6 missense variants linked to putative Lynch syndrome kindreds (e.g., p.Pro1087His, p.Arg1095His) retain normal MMR activity in vitro and correlate with reduced penetrance or later onset, underscoring the need for functional confirmation of unclassified variants (PMID:17594722).

Integration & Clinical Utility

Genetic testing for Lynch syndrome should include MSH6 sequencing and deletion/duplication analysis, with tumor immunohistochemistry or microsatellite instability as prescreening. MSH6 variant carriers benefit from colonoscopic surveillance starting by age 30–35 y and consideration of risk‐reducing strategies for endometrial cancer. Functional assays remain crucial for classification of novel missense changes.

Key Take-home: Germline MSH6 pathogenic variants are definitively associated with autosomal dominant Lynch syndrome; accurate variant interpretation integrating segregation, tumor studies, and functional assays is essential for risk assessment and management.

References

• Human genome variation • 2022 • An MSH6 germline pathogenic variant p.Gly162Ter associated with Lynch syndrome. PMID:36289196
• Molecular genetics & genomic medicine • 2023 • Characterization of a germline variant MSH6 c.4001G>C in a Lynch syndrome family. PMID:36691871
• Clinical cancer research • 2010 • MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer. PMID:20924129
• Familial cancer • 2010 • An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC. PMID:19851887
• Carcinogenesis • 1997 • Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. PMID:9054582
• Human mutation • 2007 • Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. PMID:17594722

Evidence Based Scoring (AI generated)