MLH3
Overview
MLH3 (MutL homolog 3) encodes a MutL family protein that forms heterodimers with MLH1 and participates in DNA mismatch repair (MMR). It plays a secondary role compared to the major MMR heterodimers (MLH1–PMS2, MLH1–PMS1), but loss-of-function variants have been identified in colorectal and other cancers. Its contribution to the hypermutator phenotype relative to canonical MMR deficiency remains an open question.
Alterations observed in the corpus
- Somatic mutation in pancreatic acinar cell carcinomas; identified in ACINAR01 (MSI-H) and other tumors; pathogenic significance unclear and did not clearly correlate with elevated mutation burden PMID:24293293
- MLH3 part of mismatch-repair/MMR pathway alterations identified in a 109-case PDA WES cohort PMID:25855536
Cancer types (linked)
- Pancreatic acinar cell carcinoma — somatic MLH3 mutations observed; relationship to MSI phenotype uncertain PMID:24293293
Co-occurrence and mutual exclusivity
- Co-mutated with MSH2 biallelic inactivation in MSI-H pancreatic acinar cell carcinoma ACINAR01 PMID:24293293
Therapeutic relevance
- MMR deficiency context may inform immune-checkpoint inhibitor candidacy, but MLH3 mutations alone have not been validated as predictive biomarkers in this corpus.
Open questions
- Whether MLH3 mutations alone are sufficient to drive MSI or require co-occurring MMR defects remains unresolved PMID:24293293
Sources
This page was processed by crosslinker on 2026-05-14. - PMID:25855536
This page was processed by crosslinker on 2026-05-14.