{"entity":{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","aka":["MMR proteins","mismatch repair","MLH1","MSH2","MSH6","PMS2","Lynch syndrome genes"],"tldr":"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.","asOf":"2026-09-23","wikipedia":"https://en.wikipedia.org/wiki/DNA_mismatch_repair","links":[{"label":"HGNC HGNC:7127","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7127"},{"label":"HGNC HGNC:7325","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7325"},{"label":"HGNC HGNC:7329","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7329"},{"label":"HGNC HGNC:9122","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:9122"}],"tags":["biomarker-parent"],"related":["msi-high","dmmr-ihc"],"cancers":["colorectal","endometrial","endometrial-mmr-deficient","gastric-msi-high","tnbc","pancreatic","gallbladder"],"sections":[],"technologies":[],"targets":[],"drugs":["pembrolizumab","dostarlimab","nivolumab"],"companies":[],"institutions":[],"pathways":[],"terms":["msi","mss-pmmr","mlh1-promoter-methylation","lynch-syndrome"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-ren-tnbc-mmr-msi-440-front-oncol-2021","paper-kurata-japanese-tnbc-msi-breast-cancer-2020","paper-staaf-tnbc-whole-genome-scan-b-nat-med-2019","paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","paper-singhi-targeted-genome-profiling-3594-pdac-gastroenterology-2019","paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","paper-philip-kras-wild-type-pancreatic-ccr-2022","paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","paper-keynote-158-pembrolizumab-msi-high-noncolorectal-jco-2020","paper-tcga-colorectal-comprehensive-characterization-nature-2012","paper-giannakis-genomic-correlates-immune-colorectal-cell-rep-2016","paper-venderbosch-mmr-braf-metastatic-colorectal-pooled-ccr-2014","paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009","paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009","paper-moreira-lynch-syndrome-identification-jama-2012","paper-suryavanshi-indian-gallbladder-genomics-jco-go-2025","paper-goeppert-cholangiocarcinoma-mmr-deficiency-bjc-2019","paper-weinberg-biliary-profiling-jgo-2019"],"journals":[],"dependsOn":[],"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)."],"symbol":"MLH1, MSH2, MSH6, PMS2","role":[],"sources":[],"specificity":"tumour-associated","distribution":"many-types","tumourAgnostic":true,"specificityNote":"Tumour-associated overexpression or amplification: 1 of 2 label readouts filed under it score protein level or gene copies (dMMR (mismatch repair deficiency by IHC)), so the medicines rely on the tumour carrying more of it than normal tissue. HPA MLH1: RNA low tissue specificity; high antibody staining in 32 normal tissues; highest cancer staining cervical cancer (7 of 11 high). HPA MSH2: RNA low tissue specificity; high antibody staining in 2 normal tissues; highest cancer staining glioma (4 of 12 high). HPA MSH6: RNA low tissue specificity; high antibody staining in 35 normal tissues; highest cancer staining breast cancer (11 of 11 high). HPA PMS2: RNA low tissue specificity; high antibody staining in 3 normal tissues; highest cancer staining glioma (3 of 12 high). Distribution: 4 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Biliary tract cancer (all types), Colorectal cancer, Endometrial cancer, Gastric & gastro-oesophageal junction cancer); approvals of single-target medicines aimed at it also list Pancreatic ductal adenocarcinoma, Breast cancer (all types), Lung cancer (all types), Skin cancer (all types) and more, not counted; Open Targets associates it with 27 specific cancer types at or above 0.5 (Lynch syndrome, colorectal cancer, mismatch repair cancer syndrome 1, Muir-Torre syndrome, colon carcinoma, mismatch repair cancer syndrome and more). Tissue-agnostic: dMMR (mismatch repair deficiency by IHC) threshold \"MSI-H or dMMR, tumour-agnostic\" for Pembrolizumab is tissue-agnostic; MSI-high (microsatellite instability by PCR or sequencing) threshold \"MSI-H or dMMR, tumour-agnostic\" for Pembrolizumab is tissue-agnostic; Pembrolizumab US 2017: \"MSI-H/dMMR solid tumours (tumour-agnostic)\". (Rule 3 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"dMMR (mismatch repair deficiency by IHC) label threshold","url":"https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287","note":"MSI-H or dMMR, tumour-agnostic"},{"label":"Human Protein Atlas MLH1 tissue","url":"https://www.proteinatlas.org/ENSG00000076242-MLH1/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MLH1 pathology","url":"https://www.proteinatlas.org/ENSG00000076242-MLH1/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MSH2 tissue","url":"https://www.proteinatlas.org/ENSG00000095002-MSH2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MSH2 pathology","url":"https://www.proteinatlas.org/ENSG00000095002-MSH2/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MSH6 tissue","url":"https://www.proteinatlas.org/ENSG00000116062-MSH6/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas MSH6 pathology","url":"https://www.proteinatlas.org/ENSG00000116062-MSH6/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas PMS2 tissue","url":"https://www.proteinatlas.org/ENSG00000122512-PMS2/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Human Protein Atlas PMS2 pathology","url":"https://www.proteinatlas.org/ENSG00000122512-PMS2/pathology","note":"patients per staining level per cancer type (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000076242 associations","url":"https://platform.opentargets.org/target/ENSG00000076242/associations","note":"cancer associations at or above 0.5 (CC0)"},{"label":"Open Targets ENSG00000095002 associations","url":"https://platform.opentargets.org/target/ENSG00000095002/associations","note":"cancer associations at or above 0.5 (CC0)"}],"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.","whereFound":["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%"],"targetClass":"enzyme","prevalence":[{"cancerId":"tnbc","pct":"0-2","measure":"Microsatellite instability or mismatch repair deficiency","source":"https://doi.org/10.3389/fonc.2021.570623","note":"No MSI-high tumour among 195 by PCR and one mismatch-repair-deficient tumour (lost MSH2) among 440 by IHC in Chinese TNBC (Ren 2021); 2 of 228 Japanese TNBCs MSI-high, 0.9% (Kurata 2020); about 4.7% of HRDetect-low tumours, roughly 1.7% of all 237 whole genomes, mismatch-repair deficient (Staaf 2019); cBioPortal: MSIsensor score 10 or more in 3 of 122 triple-negative exomes in brca_tcga_pan_can_atlas_2018, an algorithmic call not confirmed by PCR."},{"cancerId":"pancreatic","pct":"0.5-2","measure":"Mismatch repair deficiency or microsatellite instability","source":"https://doi.org/10.1158/1078-0432.CCR-17-3099","note":"7 of 833, 0.8%, all with Lynch syndrome, 4 of 7 benefiting from checkpoint blockade (Hu 2018, Clin Cancer Res); MSI-high and/or TMB-high in 0.5% of 2,563 assessed (Singhi 2019); 1 to 2% across 34 studies and 8,323 patients, associated with medullary and colloid histology and KRAS/TP53 wild-type background (Luchini 2021); 4.7% of KRAS wild-type against 0.7% of KRAS-mutant tumours (Philip 2022); cBioPortal: MSI_TYPE unstable in 6 of 1,119 reported samples and MSIsensor score 10 or more in 10 of 2,314 in pdac_msk_2024; 2 of 323 reported in pancreas_msk_2024; no TCGA sample reached MANTIS 0.4. Germline MLH1 0.13% of 3,030, odds ratio 6.66 (Hu 2018, JAMA)."},{"cancerId":"colorectal","pct":"5-15","measure":"Microsatellite instability or mismatch repair deficiency","source":"https://doi.org/10.1038/nature11252","note":"Stage matters more than anything else. In unselected surgical series: 38 of 276, 13.8%, MSI-high in the TCGA cohort with a further 44 MSI-low (Cancer Genome Atlas Network 2012); 91 of 529, 17.2%, in the 619-exome prospective cohort (Giannakis 2016); 770 of 7,217, 10.7%, in crc_msk_2026, which splits into 710 of 5,138 primaries (13.8%) and 59 of 2,045 metastases (2.9%); 125 of 1,513, 8.3%, in crc_eo_2020; 76 of 1,015, 7.5%, in crc_sysucc_2022 (cBioPortal). In first-line metastatic trial populations it collapses: 153 of 3,063, 5.0%, pooled across CAIRO, CAIRO2, COIN and FOCUS (Venderbosch 2014) and 18 of 515, 3.5%, in a phase 3 advanced cohort, 13 of them from MLH1 promoter hypermethylation (Koopman 2009)."},{"cancerId":"gallbladder","pct":"0.6-2.5","measure":"Microsatellite instability (MSI-high)","source":"https://www.cbioportal.org/study/summary?id=gbc_mskcc_2022","note":"6 of 244 samples, 2.5%, called unstable by MSIsensor in cBioPortal gbc_mskcc_2022; 0.6% (2 of 170 tested) in Indian patients (Suryavanshi 2025); 1.3% (4 of 308) in Western cholangiocarcinoma by mononucleotide markers (Goeppert 2019); gallbladder and intrahepatic tumours carried more MSI-high, PD-L1 and TMB-high than extrahepatic (Weinberg 2019)."}]},"route":"/targets/mmr/","neighbours":{"biomarker":[{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","route":"/biomarkers/dmmr-ihc/"},{"id":"msi-high","kind":"biomarker","name":"MSI-high (microsatellite instability by PCR or sequencing)","route":"/biomarkers/msi-high/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gallbladder","kind":"cancer","name":"Gallbladder cancer","route":"/cancers/gallbladder/"},{"id":"gastric-msi-high","kind":"cancer","name":"Microsatellite-unstable (MSI-high) gastric cancer","route":"/cancers/gastric-msi-high/"},{"id":"endometrial-mmr-deficient","kind":"cancer","name":"Mismatch-repair-deficient endometrial cancer","route":"/cancers/endometrial-mmr-deficient/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"tnbc","kind":"cancer","name":"Triple-negative breast cancer (TNBC)","route":"/cancers/tnbc/"}],"drug":[{"id":"dostarlimab","kind":"drug","name":"Dostarlimab","route":"/drugs/dostarlimab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"term":[{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"mss-pmmr","kind":"term","name":"Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)","route":"/terms/mss-pmmr/"},{"id":"mlh1-promoter-methylation","kind":"term","name":"MLH1 promoter methylation (sporadic versus Lynch mismatch repair loss)","route":"/terms/mlh1-promoter-methylation/"}],"paper":[{"id":"paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","kind":"paper","name":"Association Between Inherited Germline Mutations in Cancer 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deficiency","route":"/key-papers/paper-cercek-dostarlimab-rectal-nejm-2022/"},{"id":"paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014","kind":"paper","name":"Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer","route":"/key-papers/paper-pritchard-complex-msh2-msh6-hypermutated-prostate-nat-commun-2014/"},{"id":"paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021","kind":"paper","name":"Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications","route":"/key-papers/paper-luchini-msi-dmmr-pancreatic-systematic-review-gut-2021/"},{"id":"paper-tcga-colorectal-comprehensive-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal 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