{"entity":{"id":"mlh1","kind":"target","name":"MLH1","aka":["mutL homolog 1","DNA mismatch repair protein Mlh1","HNPCC","FCC2","HNPCC2","MLH-1","COCA2"],"tldr":"MLH1 (DNA mismatch repair protein Mlh1) is a gene. The public catalogues list it as a drug target, a biomarker and a DNA repair gene, and clinical evidence ties its variants to diagnosis, prognosis or drug response. Tied to Colorectal cancer, Ovarian cancer, Endometrial cancer and 4 more.","summary":"Heterodimerises with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2.\n\nCIViC holds 29 clinical evidence items and 0 assertions across 31 variants, naming Nivolumab and Oxaliplatin. Open Targets scores its association with cancer at 0.92 (direct and indirect evidence; datatypes genetic literature 0.92, affected pathway 0.61, literature 0.99, genetic association 0.94, somatic mutation 0.97, animal model 0.61). In OnCo, 1 product record names it (VENTANA MMR RxDx Panel).","asOf":"2026-09-23","links":[{"label":"HGNC HGNC:7127","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7127"},{"label":"UniProt P40692","url":"https://www.uniprot.org/uniprotkb/P40692/entry"},{"label":"NCBI Gene 4292","url":"https://www.ncbi.nlm.nih.gov/gene/4292"},{"label":"Ensembl ENSG00000076242","url":"https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000076242"}],"tags":["cancer-genes-wave"],"related":["civic","open-targets"],"cancers":["colorectal","ovarian","endometrial","breast-cancer","gastric","skin-cancer","lung-cancer"],"sections":[],"technologies":[],"targets":[],"drugs":["ventana-mmr-rxdx"],"companies":[],"institutions":[],"pathways":["colorectal-cancer-signalling","endometrial-cancer-signalling","mismatch-repair-msi","epigenetic-reprogramming"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Written by scripts/fetch-cancer-genes.ts from CIViC, Open Targets, IntOGen, HGNC and UniProt; the function text is UniProt's, condensed and in UK spelling. Roles: CIViC lists 2 therapies; CIViC holds 29 clinical evidence items on its variants; UniProt keyword \"DNA repair\". Evidence tier \"clinical-evidence\" is the strongest of those signals.","Prevalence not recorded: none of the sources gives a positivity rate.","Diseases the sources name that have no OnCo cancer page yet, so they are not linked: Lynch Syndrome; Villous Adenoma.","Colorectal cancer: MLH1 is the gene behind most mismatch repair deficiency, and in sporadic cases it is silenced rather than mutated. Promoter hypermethylation accounts for the majority of sporadic microsatellite-unstable cancers and is reversible in cell lines (Herman 1998), and it travels with the CIMP phenotype and BRAF V600E (odds ratio 203; Weisenberger 2006). An MLH1-deficient tumour is therefore tested for BRAF V600E or MLH1 methylation before a family is investigated for Lynch syndrome."],"provenance":{"editedBy":"scripts/fetch-cancer-genes.ts (CIViC, Open Targets, IntOGen, HGNC, UniProt)","editedOn":"2026-09-23"},"symbol":"MLH1","role":["drug-target","biomarker","dna-repair"],"evidenceTier":"clinical-evidence","sources":[{"label":"HGNC HGNC:7127","url":"https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7127","note":"approved symbol, name, aliases, locus and cross-references (hgnc_complete_set.txt)"},{"label":"UniProt P40692","url":"https://www.uniprot.org/uniprotkb/P40692/entry","note":"protein name, function text, keywords and locations (REST API)"},{"label":"CIViC gene MLH1","url":"https://civicdb.org/features/3532","note":"29 evidence items, 0 assertions, 31 variants; diseases: Colorectal Cancer, Endometrial Cancer, Stomach Carcinoma, Cancer, Lynch Syndrome and 1 more (GraphQL API, CC0)"},{"label":"Open Targets ENSG00000076242","url":"https://platform.opentargets.org/target/ENSG00000076242/associations","note":"association with cancer (MONDO_0004992) 0.92; per-cancer scores at or above 0.5: colorectal cancer 0.91, gastric cancer 0.63, ovarian cancer 0.72, endometrial cancer 0.69, skin cancer 0.55, breast cancer 0.67 (GraphQL API, CC0)"}],"specificity":"germline-variant","distribution":"many-types","specificityNote":"Germline variant: UniProt lists Lynch syndrome 2 (LYNCH2) under involvement in disease, and the record is a DNA repair gene; the medicines linked to it act through the loss (synthetic lethality) or use the variant to pick patients. HPA MLH1: RNA low tissue specificity; high antibody staining in 32 normal tissues; highest cancer staining cervical cancer (7 of 11 high). Distribution: 7 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Colorectal cancer, Ovarian cancer, Endometrial cancer, Breast cancer (all types), Gastric & gastro-oesophageal junction cancer, Skin cancer (all types), Lung cancer (all types)); Open Targets associates it with 19 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). (Rule 2 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"UniProt P40692","url":"https://www.uniprot.org/uniprotkb/P40692/entry","note":"involvement in disease"},{"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":"Open Targets ENSG00000076242 associations","url":"https://platform.opentargets.org/target/ENSG00000076242/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:7127","ensembl":"ENSG00000076242","uniprot":"P40692","entrez":"4292","firstDescribed":1994,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Bronner C.E. et al, Nature, 1994, \"Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/8145827/","biology":"Heterodimerises with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Location: Nucleus; Chromosome (UniProt). Locus 3p22.2 (HGNC).","whereFound":["Colorectal cancer: Open Targets association 0.91 with colorectal cancer (MONDO_0005575); CIViC evidence names this disease","Ovarian cancer: Open Targets association 0.72 with ovarian cancer (MONDO_0008170)","Endometrial cancer: Open Targets association 0.69 with endometrial cancer (MONDO_0011962); CIViC evidence names this disease","Breast cancer: Open Targets association 0.67 with breast cancer (MONDO_0007254)","Gastric & gastro-oesophageal junction cancer: Open Targets association 0.63 with gastric cancer (MONDO_0001056); CIViC evidence names this disease","Skin cancer: Open Targets association 0.55 with skin cancer (MONDO_0002898)"],"targetClass":"other","prevalence":[]},"route":"/targets/mlh1/","neighbours":{"collection":[{"id":"civic","kind":"collection","name":"CIViC","route":"/collections/civic/"},{"id":"open-targets","kind":"collection","name":"Open Targets Platform","route":"/collections/open-targets/"}],"cancer":[{"id":"breast-cancer","kind":"cancer","name":"Breast cancer (all types)","route":"/cancers/breast-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"endometrial","kind":"cancer","name":"Endometrial cancer","route":"/cancers/endometrial/"},{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"},{"id":"skin-cancer","kind":"cancer","name":"Skin cancer (all types)","route":"/cancers/skin-cancer/"}],"drug":[{"id":"ventana-mmr-rxdx","kind":"drug","name":"VENTANA MMR RxDx Panel","route":"/drugs/ventana-mmr-rxdx/"}],"pathway":[{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"endometrial-cancer-signalling","kind":"pathway","name":"Endometrial cancer (KEGG map)","route":"/pathways/endometrial-cancer-signalling/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"paper":[{"id":"paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018","kind":"paper","name":"Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer","route":"/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/"},{"id":"paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","kind":"paper","name":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer","route":"/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/"},{"id":"paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009","kind":"paper","name":"Deficient mismatch repair system in patients with sporadic advanced colorectal cancer","route":"/key-papers/paper-koopman-deficient-mismatch-repair-advanced-colorectal-bjc-2009/"},{"id":"paper-shindo-germline-sporadic-pancreatic-jco-2017","kind":"paper","name":"Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma","route":"/key-papers/paper-shindo-germline-sporadic-pancreatic-jco-2017/"},{"id":"paper-wardell-biliary-drivers-germline-j-hepatol-2018","kind":"paper","name":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","route":"/key-papers/paper-wardell-biliary-drivers-germline-j-hepatol-2018/"},{"id":"paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018","kind":"paper","name":"Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations","route":"/key-papers/paper-hu-mismatch-repair-deficiency-pancreatic-adenocarcinoma-ccr-2018/"},{"id":"paper-moreira-lynch-syndrome-identification-jama-2012","kind":"paper","name":"Identification of Lynch syndrome among patients with colorectal cancer","route":"/key-papers/paper-moreira-lynch-syndrome-identification-jama-2012/"},{"id":"paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998","kind":"paper","name":"Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma","route":"/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/"},{"id":"paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019","kind":"paper","name":"Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines","route":"/key-papers/paper-nicolosi-germline-variants-prostate-testing-guidelines-jama-oncol-2019/"},{"id":"paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019","kind":"paper","name":"Prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade","route":"/key-papers/paper-abida-msi-prostate-checkpoint-blockade-jama-oncol-2019/"}]}}