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.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
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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 (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. 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
0 submitted variants 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
Analysing Outcomes After Prostate Cancer Diagnosis and Treatment in Carriers of Rare Germline Mutations
RECRUITINGThe PROFILE Study: Germline Genetic Profiling: Correlation With Targeted Prostate Cancer Screening and Treatment
RECRUITINGCascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome
ACTIVE NOT RECRUITINGEC_ItaLynch: Mainstreaming the Diagnosis of Lynch Syndrome
NOT YET RECRUITINGDetermining the Prevalence of Muir-Torre Syndrome in Patients With Lynch Syndrome
NOT YET RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGProspective Multicenter Registry Study to Assess the Frequency of Lynch Syndrome Among Patients With Colorectal Cancer
RECRUITINGUrothelial Cancer Screening in Individuals With Lynch Syndrome Using a Urine Tumor DNA Panel (LS-URO Study)
RECRUITINGLiquid Biopsy and Machine Learning for Early Colorectal Cancer, Adenomas, Lynch Cancers, and Residual Disease Detection
RECRUITINGA Modular Multi-Basket Trial to Improve Personalized Medicine in Cancer Patients (Basket of Baskets)
RECRUITINGPancreatic Cancer Early Detection Consortium
RECRUITINGThe Cancer of the Pancreas Screening-5 CAPS5)Study
RECRUITINGExternal Resources
Links to major genomics databases and tools