MLH1
Chr 3ARADmutL homolog 1
Also known as: COCA2, FCC2, HNPCC, HNPCC2, LYNCH2, MLH-1, MMRCS1, hMLH1
The MLH1 protein heterodimerizes with PMS2 to form MutL alpha, a key component of the DNA mismatch repair system that introduces single-strand breaks near DNA mismatches to initiate repair by exonucleases. Mutations cause Lynch syndrome, mismatch repair cancer syndrome, and Muir-Torre syndrome with both autosomal dominant and autosomal recessive inheritance patterns. The gene is highly constrained against loss-of-function variants (pLI near 0, LOEUF 0.575), reflecting its essential role in maintaining genomic stability.
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 (dominant-negative, gain-of-function 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.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
MLH1 · 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