MSH2
Chr 2ADARmutS homolog 2
Also known as: COCA1, FCC1, HNPCC, HNPCC1, LCFS2, LYNCH1, MMRCS2, MSH-2
MSH2 encodes a component of the post-replicative DNA mismatch repair system that forms heterodimers (MutS alpha and beta) to recognize and bind DNA mismatches, initiating repair processes. Mutations cause Lynch syndrome 1, mismatch repair cancer syndrome 2, and Muir-Torre syndrome with both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants (pLI 0.90, LOEUF 0.33), reflecting its critical role in maintaining genomic stability.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
600 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 | 64 | 0 | 15 | 0 | 79 |
Likely Pathogenic | 11 | 1 | 8 | 0 | 20 |
VUS | 7 | 153 | 23 | 3 | 186 |
Likely Benign | 1 | 40 | 94 | 78 | 213 |
Benign | 0 | 7 | 12 | 66 | 85 |
Conflicting | — | 5 | |||
| Total | 83 | 201 | 152 | 147 | 588 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MSH2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
The IMPACT Study - Identification of Men With a Genetic Predisposition to ProstAte Cancer
ACTIVE NOT RECRUITINGCascade Testing in Families With Newly Diagnosed Hereditary Breast and Ovarian Cancer Syndrome
ACTIVE NOT RECRUITINGA Prospective Registry for Patients at High-Risk for Pancreatic Cancer
RECRUITINGSmall Bowel Capsule Endoscopy in Lynch Syndrome
RECRUITINGExoLuminate Study for Early Detection of Pancreatic Cancer
RECRUITINGAbiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients With Metastatic Castration-Resistant Prostate Cancer With DNA Repair Defects
ACTIVE NOT RECRUITINGLiquid Biopsy and Machine Learning for Early Colorectal Cancer, Adenomas, Lynch Cancers, and Residual Disease Detection
RECRUITINGPancreatic Cancer Early Detection Consortium
RECRUITINGPancreatic Cancer Genetics
RECRUITINGA Modular Multi-Basket Trial to Improve Personalized Medicine in Cancer Patients (Basket of Baskets)
RECRUITINGLynch Syndrome X-Talk of Enteral Mucosa With Immune System
RECRUITINGTAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer
RECRUITINGExternal Resources
Links to major genomics databases and tools