# Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)

Source: https://onco.cc/targets/mmr/  
OnCo record `mmr` (Target). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The four mismatch repair proteins proofread newly copied DNA; when a tumour loses one of them its DNA fills with small errors, and that state (dMMR or MSI-high) is what lets immunotherapy work across many cancers.

## Summary

MLH1, MSH2, MSH6 and PMS2 form the MutS and MutL complexes that recognise and excise base mismatches and slipped repeats after replication. Loss of any one, by germline mutation (Lynch syndrome), somatic mutation or MLH1 promoter methylation, produces mismatch repair deficiency, read directly by immunohistochemistry for the four proteins or indirectly as microsatellite instability by PCR or sequencing. The two readouts under this record carry the label thresholds for pembrolizumab, nivolumab, ipilimumab, dostarlimab and durvalumab and the companion diagnostics that report them.

## Fields

- Kind: Target
- Last checked: 2026-09-23
- Also known as: MMR proteins; mismatch repair; MLH1; MSH2; MSH6; PMS2; Lynch syndrome genes
- Tags: biomarker-parent
- Symbol: MLH1, MSH2, MSH6, PMS2
- Class: enzyme
- Biology: Deficient repair raises the mutation rate a hundredfold and produces frameshift neoantigens in repeat-containing genes, which is the mechanistic basis for checkpoint inhibitor sensitivity.
- Where found: Colorectal cancer (about 15 percent, most sporadic through MLH1 methylation); Endometrial cancer (about 25 to 30 percent); Gastric, small bowel, urothelial and other Lynch-spectrum tumours; Triple-negative breast cancer: microsatellite instability or mismatch repair deficiency 0-2%; Pancreatic ductal adenocarcinoma: mismatch repair deficiency or microsatellite instability 0.5-2%; Colorectal cancer: microsatellite instability or mismatch repair deficiency 5-15%; Gallbladder cancer: microsatellite instability (msi-high) 0.6-2.5%

## Notes

- Per-gene identifiers from HGNC: MLH1 HGNC:7127, ENSG00000076242, UniProt P40692; MSH2 HGNC:7325, ENSG00000095002, UniProt P43246; MSH6 HGNC:7329, ENSG00000116062, UniProt P52701; PMS2 HGNC:9122, ENSG00000122512, UniProt P54278.
- Triple-negative breast cancer: MSI-high in 0 of 195 Chinese (Ren 2021) and 2 of 228 Japanese TNBCs (Kurata 2020); about 4.7% of HRDetect-low genomes were mismatch repair-deficient (Staaf 2019). The tumour-agnostic pembrolizumab route almost never applies; TMB and PD-L1 are the immunotherapy biomarkers in this cancer.
- Pancreatic ductal adenocarcinoma: deficiency in about 1 to 2% and in 0.8% of 833 MSK patients, all of whom had Lynch syndrome, with 4 of 7 benefiting from checkpoint blockade (Hu 2018, Clin Cancer Res; Luchini 2021). It is enriched in medullary and colloid histology and in KRAS/TP53 wild-type tumours, so those are the cases to test by immunohistochemistry with PCR for doubtful results. Pembrolizumab's tumour-agnostic indication is the only approved immunotherapy route here (Marabelle 2020).
- Colorectal cancer: deficient in 10 to 15% of resected disease but only about 5% of first-line metastatic disease (153 of 3,063; Venderbosch 2014) and 3.5% in one advanced cohort (Koopman 2009), because these tumours metastasise less readily. Sporadic cases come from CIMP-associated MLH1 promoter methylation, almost always with BRAF V600E (Weisenberger 2006, Herman 1998); inherited cases are Lynch syndrome, including 3' EPCAM deletions that silence MSH2 in cis (Ligtenberg 2009). Testing every colorectal cancer finds 100% of Lynch syndrome carriers against 87.8% for the Bethesda guidelines (Moreira 2012), so universal four-protein immunohistochemistry is now standard and identifies the immunotherapy population as a by-product. About a third of deficient tumours still fail checkpoint blockade, and biallelic B2M or HLA loss is the documented escape route (Grasso 2018).
- Gallbladder cancer: MSI-high in 6 of 244 samples (2.5%, MSIsensor) in cBioPortal gbc_mskcc_2022 and 0.6% (2 of 170) of Indian patients (Suryavanshi 2025); 1.3% in Western cholangiocarcinoma (Goeppert 2019).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/DNA_mismatch_repair
- HGNC HGNC:7127: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7127
- HGNC HGNC:7325: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7325
- HGNC HGNC:7329: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7329
- HGNC HGNC:9122: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9122

## Connected records

- biomarkers: [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/), [MSI-high (microsatellite instability by PCR or sequencing)](https://onco.cc/biomarkers/msi-high/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Gallbladder cancer](https://onco.cc/cancers/gallbladder/), [Microsatellite-unstable (MSI-high) gastric cancer](https://onco.cc/cancers/gastric-msi-high/), [Mismatch-repair-deficient endometrial cancer](https://onco.cc/cancers/endometrial-mmr-deficient/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- drugs: [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- terms: [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)](https://onco.cc/terms/mlh1-promoter-methylation/)
- key papers: [Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer](https://onco.cc/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/), [Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-connor-mutational-signatures-immune-pancreatic-jama-oncol-2017/), [CAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years](https://onco.cc/key-papers/paper-capp2-aspirin-lynch-lancet-2020/), [Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency](https://onco.cc/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/), [Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer](https://onco.cc/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/), [Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications](https://onco.cc/key-papers/paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021/), [Comprehensive molecular characterization of human colon and rectal cancer](https://onco.cc/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/), [CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer](https://onco.cc/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/), [Deficient mismatch repair system in patients with sporadic advanced colorectal cancer](https://onco.cc/key-papers/paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009/), [Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features](https://onco.cc/key-papers/paper-missiaglia-distal-proximal-colon-cancers-ann-oncol-2014/), [Genetic mechanisms of immune evasion in colorectal cancer](https://onco.cc/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/), [Genomic correlates of immune-cell infiltrates in colorectal carcinoma](https://onco.cc/key-papers/paper-giannakis-genomic-correlates-immune-colorectal-cell-rep-2016/), [Genomic profiling of Indian gallbladder carcinoma: mutational insights in a high-incidence population](https://onco.cc/key-papers/paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025/), [Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1](https://onco.cc/key-papers/paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009/), [Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations](https://onco.cc/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/), [Identification of Lynch syndrome among patients with colorectal cancer](https://onco.cc/key-papers/paper-moreira-lynch-syndrome-identification-jama-2012/), [Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability](https://onco.cc/key-papers/paper-markowitz-tgfbr2-inactivation-msi-colon-science-1995/), [Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma](https://onco.cc/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/), [Integrative analyses of colorectal cancer show Immunoscore is a stronger predictor of patient survival than microsatellite instability](https://onco.cc/key-papers/paper-mlecnik-immunoscore-msi-colorectal-immunity-2016/), [KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer](https://onco.cc/key-papers/paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020/), [KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer](https://onco.cc/key-papers/paper-keynote-177-nejm-2020/), [Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ](https://onco.cc/key-papers/paper-le-mmr-deficiency-pd1-nejm-2015/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [Microsatellite instability in Japanese female patients with triple-negative breast cancer](https://onco.cc/key-papers/paper-kurata-japanese-tnbc-msi-breast-cancer-2020/), [Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients](https://onco.cc/key-papers/paper-ren-tnbc-mmr-msi-440-front-oncol-2021/), [Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma](https://onco.cc/key-papers/paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019/), [Mismatch repair status and BRAF mutation status in metastatic colorectal cancer: a pooled analysis of the CAIRO, CAIRO2, COIN and FOCUS studies](https://onco.cc/key-papers/paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014/), [Molecular biomarkers for the evaluation of colorectal cancer: guideline from ASCP, CAP, AMP and ASCO](https://onco.cc/key-papers/paper-sepulveda-molecular-biomarkers-colorectal-guideline-jco-2017/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [Molecular profiling of biliary cancers reveals distinct molecular alterations and potential therapeutic targets](https://onco.cc/key-papers/paper-weinberg-biliary-profiling-jgo-2019/), [MSH2 loss in primary prostate cancer](https://onco.cc/key-papers/paper-guedes-msh2-loss-primary-prostate-ccr-2017/), [NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients](https://onco.cc/key-papers/paper-niche-2-nejm-2024/), [Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142)](https://onco.cc/key-papers/paper-overman-checkmate-142-nivolumab-dmmr-colorectal-lancet-oncol-2017/), [Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW)](https://onco.cc/key-papers/paper-andre-checkmate-8hw-nivolumab-ipilimumab-nejm-2024/), [Nonoperative management of mismatch repair-deficient tumors](https://onco.cc/key-papers/paper-cercek-nonoperative-management-mismatch-repair-deficient-tumours-nejm-2025/), [Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial](https://onco.cc/key-papers/paper-pishvaian-lancet-oncol/), [Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade](https://onco.cc/key-papers/paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019/), [Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers](https://onco.cc/key-papers/paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019/), [Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer](https://onco.cc/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/), [The consensus molecular subtypes of colorectal cancer](https://onco.cc/key-papers/paper-cms-guinney-nat-med-2015/), [The serrated pathway to colorectal carcinoma: current concepts and challenges](https://onco.cc/key-papers/paper-bettington-serrated-pathway-colorectal-histopathology-2013/), [Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study](https://onco.cc/key-papers/paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)

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