MSH6
Chr 2ADSomaticARmutS homolog 6
Also known as: GTBP, GTMBP, HNPCC5, HSAP, LYNCH5, MMRCS3, MSH-6, p160
The MSH6 protein heterodimerizes with MSH2 to form a mismatch recognition complex that binds to DNA mismatches and initiates post-replicative DNA mismatch repair. Mutations cause Lynch syndrome 5, familial endometrial cancer, and mismatch repair cancer syndrome 3 with autosomal dominant inheritance (though some cases show autosomal recessive inheritance). This gene is highly intolerant to loss-of-function variants (pLI near 1.0, LOEUF 0.498), indicating that complete loss of function is likely incompatible with normal development.
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
1200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 152 | 3 | 8 | 0 | 163 |
Likely Pathogenic | 70 | 11 | 4 | 0 | 85 |
VUS | 9 | 381 | 19 | 0 | 409 |
Likely Benign | 1 | 11 | 79 | 201 | 292 |
Benign | 1 | 5 | 6 | 30 | 42 |
Conflicting | — | 196 | |||
| Total | 233 | 411 | 116 | 231 | 1,187 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MSH6 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Small Bowel Capsule Endoscopy in Lynch Syndrome
RECRUITINGDetermining the Prevalence of Muir-Torre Syndrome in Patients With Lynch Syndrome
NOT YET RECRUITINGA Prospective Registry for Patients at High-Risk for Pancreatic Cancer
RECRUITINGKPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGIdentification of New Candidate Genes for Hereditary Predisposition to Uveal Melanoma
RECRUITINGEC_ItaLynch: Mainstreaming the Diagnosis of Lynch Syndrome
NOT YET RECRUITINGAn Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk and An Intervention to Help Patients and Their Primary Care Providers Stay Up-to-date About Uncertain Genetic Test Results
RECRUITINGVideocapsule Endoscopy in Lynch Syndrome
RECRUITINGPopulation Based Germline Testing for Early Detection and Prevention of Cancer
RECRUITINGSurgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
ACTIVE NOT RECRUITINGPatient Centered Clinical Decision Support for Hereditary Cancer Syndromes
ENROLLING BY INVITATIONExternal Resources
Links to major genomics databases and tools