MLH1

Summary

MLH1 (mutL homolog 1, HGNC:7127) is a protein-coding gene on chromosome 3p22.2, encoding DNA mismatch repair protein Mlh1 (P40692). Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). In precision oncology, MSH2 Loss OR MLH1 Loss confers sensitivity to Nivolumab in Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC).

Source: NCBI Gene 4292 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lynch syndrome (Definitive, ClinGen) — +10 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 6,394 total — 1543 pathogenic, 349 likely-pathogenic
• Phenotypes (HPO): 89
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000249

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7127
Approved symbol	MLH1
Name	mutL homolog 1
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	HNPCC, FCC2, HNPCC2, MLH-1
Ensembl gene	ENSG00000076242
Ensembl biotype	protein_coding
OMIM	120436
Entrez	4292

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 26 protein_coding, 10 nonsense_mediated_decay, 8 retained_intron

ENST00000231790, ENST00000413212, ENST00000413740, ENST00000429117, ENST00000432299, ENST00000435176, ENST00000441265, ENST00000442249, ENST00000447829, ENST00000450420, ENST00000454028, ENST00000455445, ENST00000456676, ENST00000457004, ENST00000458009, ENST00000458205, ENST00000466900, ENST00000476172, ENST00000485889, ENST00000492474, ENST00000536378, ENST00000539477, ENST00000616768, ENST00000673673, ENST00000673686, ENST00000673713, ENST00000673715, ENST00000673741, ENST00000673889, ENST00000673897, ENST00000673899, ENST00000673947, ENST00000673972, ENST00000673990, ENST00000674019, ENST00000674107, ENST00000674111, ENST00000674125, ENST00000713802, ENST00000931189, ENST00000931190, ENST00000931191, ENST00000948704, ENST00000948705

RefSeq mRNA: 23 — MANE Select: NM_000249 NM_000249, NM_001167617, NM_001167618, NM_001167619, NM_001258271, NM_001258273, NM_001258274, NM_001354615, NM_001354616, NM_001354617, NM_001354618, NM_001354619, NM_001354620, NM_001354621, NM_001354622, NM_001354623, NM_001354624, NM_001354625, NM_001354626, NM_001354627, NM_001354628, NM_001354629, NM_001354630

CCDS: CCDS2663, CCDS54562, CCDS54563

Canonical transcript exons

ENST00000231790 — 19 exons

Exon	Start	End
ENSE00001593400	37048517	37048609
ENSE00001716871	37017506	37017599
ENSE00001730188	37040186	37040294
ENSE00001747618	37042268	37042331
ENSE00001748897	37047519	37047683
ENSE00001785296	37048904	37049017
ENSE00003496022	36996619	36996709
ENSE00003516787	37012011	37012099
ENSE00003521968	37011820	37011862
ENSE00003533853	37006991	37007063
ENSE00003599036	37000955	37001053
ENSE00003633623	37008814	37008905
ENSE00003635406	37004401	37004474
ENSE00003656033	37014432	37014544
ENSE00003680564	37028784	37028932
ENSE00003688106	37025637	37026007
ENSE00003785627	37020310	37020463
ENSE00003902581	37050486	37050846
ENSE00004012715	36993518	36993663

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 94.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5146 / max 527.0253, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36041	29.2943	1811
36043	4.7952	1630
36042	1.4070	984
36044	0.0181	5

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	94.44	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.42	gold quality
deltoid	UBERON:0001476	94.37	gold quality
left ventricle myocardium	UBERON:0006566	94.30	gold quality
heart left ventricle	UBERON:0002084	93.97	gold quality
cardiac ventricle	UBERON:0002082	93.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.85	gold quality
vastus lateralis	UBERON:0001379	93.84	gold quality
quadriceps femoris	UBERON:0001377	93.78	gold quality
apex of heart	UBERON:0002098	93.60	gold quality
skeletal muscle tissue	UBERON:0001134	93.35	gold quality
heart right ventricle	UBERON:0002080	93.35	gold quality
ganglionic eminence	UBERON:0004023	93.22	gold quality
muscle organ	UBERON:0001630	92.99	gold quality
skeletal muscle organ	UBERON:0014892	92.99	gold quality
biceps brachii	UBERON:0001507	92.97	gold quality
muscle tissue	UBERON:0002385	92.79	gold quality
heart	UBERON:0000948	92.78	gold quality
muscle of leg	UBERON:0001383	92.75	gold quality
ventricular zone	UBERON:0003053	92.73	gold quality
tibia	UBERON:0000979	92.69	gold quality
calcaneal tendon	UBERON:0003701	92.62	gold quality
gastrocnemius	UBERON:0001388	92.53	gold quality
diaphragm	UBERON:0001103	92.49	gold quality
pituitary gland	UBERON:0000007	92.48	gold quality
triceps brachii	UBERON:0001509	92.45	gold quality
adenohypophysis	UBERON:0002196	92.41	gold quality
skin of hip	UBERON:0001554	92.34	gold quality
right atrium auricular region	UBERON:0006631	92.32	gold quality
corpus callosum	UBERON:0002336	92.23	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.25
E-CURD-10	no	381.53
E-MTAB-7606	no	153.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BHLHE40, BHLHE41, BRIP1, CEBPZ, CTNNBL1, DNMT1, DNMT3A, E2F4, ESR2, GLI1, GLI2, HIF1A, HOXA5, HOXD1, MAFG, MLXIP, TP53, TP73, WT1

miRNA regulators (miRDB)

23 targeting MLH1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-373-3P	99.84	70.68	1668
HSA-MIR-520E-3P	99.84	70.55	1698
HSA-MIR-372-3P	99.83	70.58	1691
HSA-MIR-520A-3P	99.83	70.59	1687
HSA-MIR-520B-3P	99.83	70.56	1699
HSA-MIR-520C-3P	99.83	70.56	1699
HSA-MIR-520D-3P	99.83	70.78	1676
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-216B-3P	98.55	67.19	1223

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• hereditary and somatic mutations in sporadic endometrial adenocarcinoma (PMID:11474654)
• mutational analysis in HNPCC (PMID:11524701)
• binds Bloom syndrome protein; nuclear localization (PMID:11691925)
• Further characterization of the mutational spectrum of MLH1 gene in HNPCC families. (PMID:11748856)
• Mutational analysis of promoters of mismatch repair genes hMSH2 and hMLH1 in hereditary nonpolyposis colorectal cancer and early onset colorectal cancer patients: identification of three novel germ-line mutations in promoter of the hMSH2 gene. (PMID:11782355)
• PMS2-MLH1 protein interactions diminished by single nucleotide polymorphisms in HNPCC (PMID:11793469)
• hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA (PMID:11809883)
• Large deletions have been detected in MLH1 in hereditary nonpolyposis colorectal cancer (HNPCC). (PMID:11857745)
• Tumor-specific promoter hypermethylation of hMLH1 may be an early event in carcinogenesis of the stomach (PMID:11872960)
• Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography (PMID:11879922)
• Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. (PMID:11897781)
• methylation density of a specific region plays an important role in gene inactivation of hMLH1 in colonic and gastric cancer cell lines (PMID:11935297)
• Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha (PMID:11948175)
• The expression of hMLH1 and hPMS1 was significantly low in some large B-cell lymphomas and in mantle cell lymphomas of the blastoid type and may be related to the natural history of these neoplasms. (PMID:11999575)
• Association of Crohn’s disease and ulcerative colitis with haplotypes of the MLH1 gene (PMID:12011151)
• Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability occur in ovarian cancer. (PMID:12014680)
• upregulation by ascorbic acid (PMID:12023887)
• Eight mutations and two polymorphisms detected in Brazilian families with suspected Hereditary Nonpolyposis Colorectal Cancer (PMID:12095971)
• Age of onset and tumor microsatellite instability (MSI) not associated with MLH1 promoter methylation may point to women with a genetic susceptibility to malignancies (PMID:12115503)
• Loss of mismatch repair protein (mainly, Mlh1) expression was detected in 21 of the 52 (40.4%) colorectal carcinomas (PMID:12177781)
• The type 1 methylation pattern affects MLH1 mRNA expression such that the majority of cases of high-frequency microsatellite instability in sporadic colorectal cancer exhibit type 1 methylation. (PMID:12203784)
• Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. (PMID:12209584)
• Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. (PMID:12384516)
• Different molecular mechanisms underlie MLH1 sequence deletions in patients with Hereditary Nonpolyposis Colorectal Neoplasms. (PMID:12402334)
• Biallelic inactivation of the MLH1 gene is a common epigenetic event in colorectal carcinogenesis when the promoter region is fully methylated. (PMID:12461746)
• mutation analysis of K-ras and beta-catenin genes related to O-6-methylguanine-DNA methyltransferase and this protein status in human gallbladder carcinoma (PMID:12469220)
• genomic deletions in both MSH2 and MLH1 genes play a considerable role in the pathogenesis of HNPCC and should be part of the routine HNPCC mutation detection protocols. (PMID:12494471)
• Mutations in the hMLH1 gene cause inactivation of the MMR gene in renal cell carcinoma. (PMID:12496483)
• Mutations in hMLH1 cause inactivation of the MMR gene in renal cell carcinoma. (PMID:12496484)
• Data show that hypermethylation of human MLH1 may play a role in the early stage of development of some gastric carcinomas. (PMID:12508345)
• We report that expression of wild-type hMLH1 protein causes 19-fold increase in mutation rates, which was due to the ability of hMLH1 to interact with E coli MutL and MutS (PMID:12513688)
• extensive methylation of hmlh1 is associated with the presence of a defective DNA mismatch repair pathway resulting in microsatellite instability in acute myeloid leukemia (PMID:12529664)
• Microsatellite instability and hypermethylation of the promoter of this protein are involved in Richter’s transformation of chronic lymphocytic leukemia. (PMID:12592341)
• CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. (PMID:12592365)
• Promoter hypermethylation represents a major mechanism of the hMLH1 gene inactivation in head and neck squamous cell carcinoma. (PMID:12605036)
• loss of hMLH1 expression in colorectal cancer patients strongly associated with increasing age (PMID:12627505)
• loss of MLH1 and MSH2 expression seen in approximately equal frequency in small intestine neoplasms with microsatellite instability (PMID:12627520)
• Novel germline mutation in MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) noted in one Uraguayan HNPCC family (PMID:12660027)
• There is mutation and methylation of this gene in gastric carcinomas with microsatellite instability. (PMID:12679904)
• Mutations of this protein show microsatellite instability in human prostatic cancer (PMID:12684669)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mlh1	ENSDARG00000025948
mus_musculus	Mlh1	ENSMUSG00000032498
rattus_norvegicus	Mlh1	ENSRNOG00000033809
drosophila_melanogaster	Mlh1	FBGN0011659
caenorhabditis_elegans		WBGENE00003373

Paralogs (3): PMS1 (ENSG00000064933), MLH3 (ENSG00000119684), PMS2 (ENSG00000122512)

Protein

Protein identifiers

DNA mismatch repair protein Mlh1 — P40692 (reviewed: P40692)

Alternative names: MutL protein homolog 1

All UniProt accessions (18): P40692, A0A087WX20, A0A669KAW3, A0A669KB03, A0A669KBB4, A0A669KBK2, A0AAQ5BGN3, A0AAQ5BGZ2, C9JZ54, E7EUC9, E9PF25, F2Z298, H0Y4N0, H0Y5L7, H0Y5U4, H0Y793, H0Y806, H0Y818

UniProt curated annotations — full annotation on UniProt →

Function. Heterodimerizes 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. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.

Subunit / interactions. Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer of MLH1 and PMS2 (MutL alpha), MLH1 and PMS1 (MutL beta) or MLH1 and MLH3 (MutL gamma). Forms a ternary complex with MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with MCM9; the interaction recruits MLH1 to chromatin. Interacts with MCM8. Interacts with PMS2; this interaction promotes MLH1 stability. Interacts with MBD4. Interacts with EXO1. Interacts with MTMR15/FAN1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.

Post-translational modifications. Acetylated. Deacetylated by HDAC6 which prevents the MutL alpha complex, formed by the MLH1-PMS2 heterodimer, from being recruited to the MutS alpha complex, formed by the MSH2-MSH6 heterodimer, leading to tolerance of DNA damage. Ubiquitinated by UBR4; leading to proteasomal degradation. This ubiquitination is counteracted by the deubiquitinase USP5.

Disease relevance. Lynch syndrome 2 (LYNCH2) [MIM:609310] A form of Lynch syndrome, an autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors of the gastrointestinal, urological and female reproductive tracts. Lynch syndrome is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, it is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by increased risk for cancers in certain tissues such as the uterus, ovary, breast, stomach, small intestine, skin, and larynx in addition to the colon. Diagnosis of classical Lynch syndrome is based on the Amsterdam criteria: 3 or more relatives affected by colorectal cancer, one a first degree relative of the other two; 2 or more generation affected; 1 or more colorectal cancers presenting before 50 years of age; exclusion of hereditary polyposis syndromes. The term ‘suspected Lynch syndrome’ or ‘incomplete Lynch syndrome’ can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. The disease is caused by variants affecting the gene represented in this entry. Mismatch repair cancer syndrome 1 (MMRCS1) [MIM:276300] An autosomal recessive form of mismatch repair cancer syndrome, a childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. The disease is caused by variants affecting the gene represented in this entry. Muir-Torre syndrome (MRTES) [MIM:158320] Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. The disease is caused by variants affecting the gene represented in this entry. Defects in MLH1 may contribute to lobular carcinoma in situ (LCIS), a non-invasive neoplastic disease of the breast. Endometrial cancer (ENDMC) [MIM:608089] A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. Disease susceptibility is associated with variants affecting the gene represented in this entry. Some epigenetic changes can be transmitted unchanged through the germline (termed ’epigenetic inheritance’). Evidence that this mechanism occurs in humans is provided by the identification of individuals in whom 1 allele of the MLH1 gene is epigenetically silenced throughout the soma (implying a germline event). These individuals are affected by Lynch syndrome but does not have identifiable mutations in MLH1, even though it is silenced, which demonstrates that an epimutation can phenocopy a genetic disease. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutL/HexB family.

Isoforms (3)

UniProt ID	Names	Canonical?
P40692-1	1	yes
P40692-2	2
P40692-3	3

RefSeq proteins (23): NP_000240, NP_001161089, NP_001161090, NP_001161091, NP_001245200, NP_001245202, NP_001245203, NP_001341544, NP_001341545, NP_001341546, NP_001341547, NP_001341548, NP_001341549, NP_001341550, NP_001341551, NP_001341552, NP_001341553, NP_001341554, NP_001341555, NP_001341556, NP_001341557, NP_001341558, NP_001341559 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002099	MutL/Mlh/PMS	Family
IPR013507	DNA_mismatch_S5_2-like	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR014762	DNA_mismatch_repair_CS	Conserved_site
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily
IPR032189	Mlh1_C	Domain
IPR036890	HATPase_C_sf	Homologous_superfamily
IPR038973	MutL/Mlh/Pms-like	Family

Pfam: PF01119, PF13589, PF16413

UniProt features (252 total): sequence variant 173, helix 23, strand 19, mutagenesis site 10, modified residue 6, turn 5, binding site 4, region of interest 3, splice variant 2, sequence conflict 2, compositionally biased region 2, initiator methionine 1, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6WBC	X-RAY DIFFRACTION	2.15
6WBA	X-RAY DIFFRACTION	2.15
3RBN	X-RAY DIFFRACTION	2.16
5U5P	X-RAY DIFFRACTION	2.17
4P7A	X-RAY DIFFRACTION	2.3
7M60	X-RAY DIFFRACTION	2.3
6WBB	X-RAY DIFFRACTION	2.66

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40692-F1	77.89	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 82–84; 100–104; 38; 63

Post-translational modifications (6): 2, 33, 241, 361, 377, 477

Mutagenesis-validated functional residues (10):

Position	Phenotype
33	abolishes acetylation; when associated with q-241, q-361 and q-377.
33	abolishes acetylation and binding affinity for msh6 and msh2; when associated with r-241, r-361 and r-377.
241	abolishes acetylation; when associated with q-33, q-361 and q-377.
241	abolishes acetylation and binding affinity for msh6 and msh2; when associated with r-33, r-361 and r-377.
361	abolishes acetylation; when associated with q-33, q-241 and q-377.
361	abolishes acetylation and binding affinity for msh6 and msh2; when associated with r-33, r-241 and r-377.
377	abolishes acetylation; when associated with q-33, q-241 and q-361.
377	abolishes acetylation and binding affinity for msh6 and msh2; when associated with r-33, r-241 and r-361.
471	affects binding to importins alpha, including kpna2, hence may affect import to the nucleus.
472	affects binding to importins alpha, including kpna2, hence may affect import to the nucleus.

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-5545483	Defective Mismatch Repair Associated With MLH1
R-HSA-5632987	Defective Mismatch Repair Associated With PMS2
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-912446	Meiotic recombination
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5358508	Mismatch Repair
R-HSA-5423599	Diseases of Mismatch Repair (MMR)
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-73894	DNA Repair
R-HSA-74160	Gene expression (Transcription)
R-HSA-9675135	Diseases of DNA repair

MSigDB gene sets: 538 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GNF2_MSH2, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_CHROMOSOME_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES

GO Biological Process (29): nuclear-transcribed mRNA poly(A) tail shortening (GO:0000289), resolution of meiotic recombination intermediates (GO:0000712), mismatch repair (GO:0006298), double-strand break repair via nonhomologous end joining (GO:0006303), male meiosis chromosome segregation (GO:0007060), homologous chromosome pairing at meiosis (GO:0007129), spermatogenesis (GO:0007283), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to bacterium (GO:0009617), female meiosis chromosome segregation (GO:0016321), somatic hypermutation of immunoglobulin genes (GO:0016446), meiotic metaphase I homologous chromosome alignment (GO:0043060), meiotic telomere clustering (GO:0045141), isotype switching (GO:0045190), negative regulation of mitotic recombination (GO:0045950), positive regulation of isotype switching to IgA isotypes (GO:0048298), positive regulation of isotype switching to IgG isotypes (GO:0048304), oogenesis (GO:0048477), meiotic spindle midzone assembly (GO:0051257), somatic recombination of immunoglobulin genes involved in immune response (GO:0002204), DNA repair (GO:0006281), response to stress (GO:0006950), DNA damage response (GO:0006974), reciprocal meiotic recombination (GO:0007131), male meiotic nuclear division (GO:0007140), somatic recombination of immunoglobulin gene segments (GO:0016447), meiotic chromosome segregation (GO:0045132), homologous chromosome segregation (GO:0045143), meiotic cell cycle (GO:0051321)

GO Molecular Function (12): chromatin binding (GO:0003682), ATP binding (GO:0005524), enzyme activator activity (GO:0008047), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), guanine/thymine mispair binding (GO:0032137), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), single-stranded DNA binding (GO:0003697), protein binding (GO:0005515), mismatched DNA binding (GO:0030983), MutSalpha complex binding (GO:0032407)

GO Cellular Component (13): synaptonemal complex (GO:0000795), male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), chiasma (GO:0005712), late recombination nodule (GO:0005715), membrane (GO:0016020), MutLalpha complex (GO:0032389), condensed chromosome (GO:0000793), condensed nuclear chromosome (GO:0000794), nuclear lumen (GO:0031981), mismatch repair complex (GO:0032300)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Mismatch Repair	2
Diseases of Mismatch Repair (MMR)	2
Transcriptional Regulation by TP53	1
Meiosis	1
Reproduction	1
Cell Cycle	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
DNA Repair	1
Diseases of DNA repair	1
Gene expression (Transcription)	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
meiotic chromosome segregation	2
homologous chromosome segregation	2
chromosome organization involved in meiotic cell cycle	2
positive regulation of isotype switching	2
binding	2
nucleus	2
nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	1
nuclear-transcribed mRNA catabolic process	1
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
DNA repair	1
double-strand break repair	1
male meiotic nuclear division	1
developmental process involved in reproduction	1
male gamete generation	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
response to other organism	1
female meiotic nuclear division	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immunoglobulins	1
meiotic metaphase chromosome alignment	1
telomere localization	1
chromosome localization to nuclear envelope involved in homologous chromosome segregation	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
regulation of mitotic recombination	1
mitotic recombination	1
negative regulation of DNA recombination	1
isotype switching to IgA isotypes	1
regulation of isotype switching to IgA isotypes	1
isotype switching to IgG isotypes	1
regulation of isotype switching to IgG isotypes	1
germ cell development	1
female gamete generation	1
spindle midzone assembly	1
meiotic nuclear division	1
meiotic cell cycle process	1
somatic diversification of immunoglobulins involved in immune response	1

Protein interactions and networks

STRING

3428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MLH1	MSH3	P20585	999
MLH1	MSH2	P43246	999
MLH1	MSH6	P52701	999
MLH1	EXO1	Q9UQ84	998
MLH1	MLH3	P49751	993
MLH1	PMS1	P54277	993
MLH1	PMS2	P54278	993
MLH1	ATM	Q13315	992
MLH1	BRIP1	Q9BX63	951
MLH1	BRCA1	P38398	930
MLH1	MBD4	O95243	921
MLH1	MUTYH	Q9UIF7	914
MLH1	BRCA2	P51587	905
MLH1	BRAF	P15056	876
MLH1	FANCD2	Q9BXW9	874

IntAct

514 interactions, top by confidence:

A	B	Type	Score
BRIP1	BRCA1	psi-mi:“MI:0914”(association)	0.980
PMS2	MLH1	psi-mi:“MI:0407”(direct interaction)	0.970
MLH1	PMS2	psi-mi:“MI:0915”(physical association)	0.970
PMS2	MLH1	psi-mi:“MI:0915”(physical association)	0.970
MLH1	BRIP1	psi-mi:“MI:0915”(physical association)	0.940
MYOG	MLH1	psi-mi:“MI:0915”(physical association)	0.890
MLH1	MYOG	psi-mi:“MI:0915”(physical association)	0.890
MLH1	RADX	psi-mi:“MI:0915”(physical association)	0.870
ZC3H11A	MLH1	psi-mi:“MI:0915”(physical association)	0.870

BioGRID (493): MLH1 (Two-hybrid), MSH3 (Two-hybrid), MYOG (Two-hybrid), PSMA1 (Two-hybrid), CXorf57 (Two-hybrid), SPERT (Two-hybrid), MLH1 (Affinity Capture-Western), MLH1 (Reconstituted Complex), MLH1 (Affinity Capture-MS), MLH1 (Two-hybrid), TRIM29 (Two-hybrid), ZC3H11A (Two-hybrid), FRMD6 (Two-hybrid), UBOX5 (Two-hybrid), API5 (Co-fractionation)

ESM2 similar proteins: A6QLK2, A6QNT8, D3ZMY7, D4A055, F1QH17, O00305, O35431, O95486, O95487, P40692, P49902, P54288, P56223, P97679, Q01973, Q0VGM9, Q13330, Q16514, Q1RMS5, Q3SWT1, Q3T174, Q3U2P1, Q3UNW5, Q3V1L4, Q5EBF1, Q5PYH5, Q5RA22, Q5RB16, Q5RE34, Q5RJZ1, Q5ZIZ4, Q61187, Q62599, Q6AY57, Q6DKB0, Q6H1L8, Q6IRE4, Q7ZWU5, Q80W47, Q80YA3

Diamond homologs: A0KGR9, A0LJK2, A1JIR3, A1QZ05, A1SZL2, A4SR27, A5F3L5, A5FW68, A5UB71, A5UFN4, A6VN10, A7FUK9, A7GE44, A8FRD3, A8G8U7, A8H8G8, A9MFP2, A9N4Y4, B0B8E9, B0BA28, B0BTY3, B0K1A3, B0K9L6, B0R2S6, B0RRZ8, B0UUU5, B1IM67, B1KSA2, B1ZZY2, B2ULE2, B2VCU8, B4T2R5, B4TFA4, B4TSF0, B5BKH9, B5F385, B5FBR6, B5FRM6, B5R0N7, B5R9B7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TP53	“up-regulates quantity”	MLH1	“transcriptional regulation”
ABL1	“up-regulates quantity by stabilization”	MLH1	phosphorylation
MLH1	“form complex”	MLH1/PMS1	binding
MLH1	“form complex”	MLH1/PMS2	binding
MLH1	“up-regulates activity”	DNA_repair

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 78 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DNA Repair	6	12.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mismatch repair	6	59.8×	3e-07

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

MLH1 is a tumor suppressor gene involved in DNA mismatch repair. Germline mutations in this gene are known to cause Lynch syndrome. The most common malignancies in Lynch syndrome are colorectal and endometrial carcinomas. In addition to germline mutations, somatic mutations in this gene have been described in colorectal and endometrial cancers.

Clinical variants and AI predictions

ClinVar

6394 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1543
Likely pathogenic	349
Uncertain significance	2150
Likely benign	1018
Benign	193

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012206	NM_000249.4(MLH1):c.1003del (p.Leu335fs)	Pathogenic
1023950	NM_000249.4(MLH1):c.1681_1686del (p.Tyr561_Gln562del)	Pathogenic
1048862	NM_000249.4(MLH1):c.497T>G (p.Leu166Ter)	Pathogenic
1048888	NM_000249.4(MLH1):c.2131dup (p.Ser711fs)	Pathogenic
1049248	NM_000249.4(MLH1):c.1039-2_1409+1del	Pathogenic
1049302	NM_000249.4(MLH1):c.1275dup (p.Gln426fs)	Pathogenic
1049396	NM_000249.4(MLH1):c.1999del (p.Asp667fs)	Pathogenic
1049508	NM_000249.4(MLH1):c.631_632del (p.Ser211fs)	Pathogenic
1049646	NM_000249.4(MLH1):c.546-2_589-59del	Pathogenic
1049670	NM_000249.4(MLH1):c.1896+1G>C	Pathogenic
1049673	NM_000249.4(MLH1):c.1367del (p.Thr455_Ser456insTer)	Pathogenic
1049886	NM_000249.4(MLH1):c.-2_116+1del	Pathogenic
1050017	NM_000249.4(MLH1):c.365del (p.Gly122fs)	Pathogenic
1050185	NM_000249.4(MLH1):c.1039-2_1409+150del	Pathogenic
1050489	NM_000249.4(MLH1):c.1770_1772delinsC (p.Leu590fs)	Pathogenic
1050518	NM_000249.4(MLH1):c.1732-2_1896+1del	Pathogenic
1050645	NM_000249.4(MLH1):c.1559-2_1667+1del	Pathogenic
1050662	NM_000249.4(MLH1):c.1559-4_1667+63del	Pathogenic
1050751	NM_000249.4(MLH1):c.995_996insA (p.Ser332fs)	Pathogenic
1065545	NM_000249.3:c.(1896+1_1897-1)_(2103+1_2104-1)dup	Pathogenic
1068445	NC_000003.11:g.(?37048472)(37050406_?)del	Pathogenic
1068446	NC_000003.11:g.(?37053301)(37059100_?)del	Pathogenic
1068563	NM_000249.4(MLH1):c.1921dup (p.Leu641fs)	Pathogenic
1068760	NM_000249.4(MLH1):c.2089dup (p.Leu697fs)	Pathogenic
1068948	NM_000249.4(MLH1):c.406A>T (p.Lys136Ter)	Pathogenic
1069159	NC_000003.11:g.(?37035033)(37035160_?)del	Pathogenic
1069316	NM_000249.4(MLH1):c.1482T>A (p.Cys494Ter)	Pathogenic
1069408	NM_000249.4(MLH1):c.1507del (p.Leu503fs)	Pathogenic
1069751	NM_000249.4(MLH1):c.2039_2040delinsAG (p.Cys680Ter)	Pathogenic
1069993	NM_000249.4(MLH1):c.2099del (p.Gln700fs)	Pathogenic

SpliceAI

2888 predictions. Top by Δscore:

Variant	Effect	Δscore
3:36993672:G:GT	donor_gain	1.0000
3:36996617:A:AG	acceptor_gain	1.0000
3:36996618:G:GA	acceptor_gain	1.0000
3:36996618:GTTT:G	acceptor_gain	1.0000
3:36996618:GTTTA:G	acceptor_gain	1.0000
3:36996707:AGGG:A	donor_loss	1.0000
3:36996708:GG:G	donor_gain	1.0000
3:36996708:GGGTA:G	donor_loss	1.0000
3:36996709:GG:G	donor_gain	1.0000
3:36996710:G:A	donor_loss	1.0000
3:36996710:G:GG	donor_gain	1.0000
3:36996711:T:TC	donor_loss	1.0000
3:37004470:TACAG:T	donor_loss	1.0000
3:37004471:ACAG:A	donor_loss	1.0000
3:37004472:CAGG:C	donor_loss	1.0000
3:37004473:AGGTA:A	donor_loss	1.0000
3:37004474:GG:G	donor_loss	1.0000
3:37004475:G:A	donor_loss	1.0000
3:37004476:T:G	donor_loss	1.0000
3:37006989:A:AG	acceptor_gain	1.0000
3:37006990:G:GG	acceptor_gain	1.0000
3:37006990:GA:G	acceptor_gain	1.0000
3:37006990:GAGCA:G	acceptor_gain	1.0000
3:37007064:G:GG	donor_gain	1.0000
3:37011814:TTCCA:T	acceptor_loss	1.0000
3:37011817:CAG:C	acceptor_loss	1.0000
3:37011818:A:AG	acceptor_gain	1.0000
3:37011818:A:C	acceptor_loss	1.0000
3:37011819:G:GG	acceptor_gain	1.0000
3:37011863:G:GG	donor_gain	1.0000

AlphaMissense

4981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:36993600:G:C	R18P	1.000
3:36993603:T:A	I19N	1.000
3:36993646:A:C	K33N	1.000
3:36993646:A:T	K33N	1.000
3:36993661:C:A	N38K	1.000
3:36993661:C:G	N38K	1.000
3:37000985:T:C	F80L	1.000
3:37000987:C:A	F80L	1.000
3:37000987:C:G	F80L	1.000
3:37001040:G:A	G98D	1.000
3:37001042:T:C	F99L	1.000
3:37001043:T:C	F99S	1.000
3:37001044:T:A	F99L	1.000
3:37001044:T:G	F99L	1.000
3:37001048:G:C	G101R	1.000
3:37001048:G:T	G101C	1.000
3:37001049:G:A	G101D	1.000
3:37001049:G:T	G101V	1.000
3:37004410:A:C	S106R	1.000
3:37004412:C:A	S106R	1.000
3:37004412:C:G	S106R	1.000
3:37004425:G:C	A111P	1.000
3:37017508:C:A	R265S	1.000
3:37017509:G:C	R265P	1.000
3:37020343:T:A	N306K	1.000
3:37020343:T:G	N306K	1.000
3:37020358:G:C	K311N	1.000
3:37020358:G:T	K311N	1.000
3:37050639:T:C	F753L	1.000
3:37050641:T:A	F753L	1.000

dbSNP variants (sampled 300 via entrez): RS1000009385 (3:36991731 C>A,T), RS1000076144 (3:37045225 G>C,T), RS1000080361 (3:36994441 C>T), RS1000089770 (3:37023791 T>A), RS1000170929 (3:36999602 G>C), RS1000221022 (3:37006802 A>C,G), RS1000225822 (3:37018971 C>T), RS1000278225 (3:37018696 C>G,T), RS1000281426 (3:36994277 T>G), RS1000285072 (3:37025331 G>A,C), RS1000443765 (3:37006563 C>T), RS1000457999 (3:36999763 T>C), RS1000537381 (3:37049947 T>C), RS1000580328 (3:37001500 A>T), RS1000588464 (3:37049638 G>A)

Disease associations

OMIM: gene MIM:120436 | disease phenotypes: MIM:609310, MIM:120435, MIM:158320, MIM:276300, MIM:167000, MIM:114480, MIM:614350, MIM:613659, MIM:211980, MIM:604370

GenCC curated gene-disease

Disease	Classification	Inheritance
Muir-Torre syndrome	Definitive	Autosomal dominant
mismatch repair cancer syndrome 1	Definitive	Autosomal recessive
Lynch syndrome 2	Definitive	Autosomal dominant
Lynch syndrome	Definitive	Autosomal dominant
ovarian cancer	Strong	Autosomal dominant
Lynch syndrome 1	Strong	Autosomal dominant
rhabdomyosarcoma	Moderate	Autosomal recessive
malignant pancreatic neoplasm	Moderate	Autosomal dominant
prostate cancer	Limited	Autosomal dominant
breast cancer	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Lynch syndrome	Definitive	AD
mismatch repair cancer syndrome 1	Definitive	AR
hereditary breast carcinoma	Refuted	AD

Mondo (29): hereditary neoplastic syndrome (MONDO:0015356), Lynch syndrome (MONDO:0005835), Lynch syndrome 2 (MONDO:0012249), Lynch syndrome 1 (MONDO:0007356), Muir-Torre syndrome (MONDO:0008018), mismatch repair cancer syndrome 1 (MONDO:0010159), colon carcinoma (MONDO:0002032), endometrial carcinoma (MONDO:0002447), breast cancer (MONDO:0007254), hereditary nonpolyposis colon cancer (MONDO:0018630), hereditary breast ovarian cancer syndrome (MONDO:0003582), colonic neoplasm (MONDO:0005401), ovarian cancer (MONDO:0008170), primary peritoneal carcinoma (MONDO:0015686), malignant colon neoplasm (MONDO:0021063)

Orphanet (10): Inherited cancer-predisposing syndrome (Orphanet:140162), Lynch syndrome (Orphanet:144), Constitutional mismatch repair deficiency syndrome (Orphanet:252202), Muir-Torre syndrome (Orphanet:587), Hereditary nonpolyposis colon cancer (Orphanet:443909), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Rare ovarian cancer (Orphanet:213500), Primary peritoneal carcinoma (Orphanet:168829), Hereditary breast cancer (Orphanet:227535), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000997	Axillary freckling
HP:0001010	Hypopigmentation of the skin
HP:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001371	Flexion contracture
HP:0001402	Hepatocellular carcinoma
HP:0001522	Death in infancy
HP:0001824	Weight loss
HP:0001909	Leukemia
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002024	Malabsorption
HP:0002027	Abdominal pain
HP:0002076	Migraine
HP:0002167	Abnormal speech pattern
HP:0002239	Gastrointestinal hemorrhage
HP:0002253	Colonic diverticula

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003158_2	Subjective response to lithium treatment	8.000000e-07
GCST004521_90	Autism spectrum disorder or schizophrenia	1.000000e-11
GCST004946_15	Schizophrenia	3.000000e-11
GCST012206_1	Proximal colorectal cancer	4.000000e-18
GCST90002401_439	Platelet distribution width	2.000000e-18
GCST90011898_158	Alanine aminotransferase levels	2.000000e-08
GCST90013405_2	Liver enzyme levels (alanine transaminase)	4.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D002294	Carcinoma, Squamous Cell	C04.557.470.200.400; C04.557.470.700.400
D003110	Colonic Neoplasms	C04.588.274.476.411.307.180; C06.301.371.411.307.180; C06.405.249.411.307.180; C06.405.469.158.356.180; C06.405.469.491.307.180
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D055847	Lynch Syndrome II	C04.700.250.500; C16.320.700.250.500
D055653	Muir-Torre Syndrome	C04.588.805.578.500; C04.700.250.500.500; C16.320.700.250.500.500; C17.800.794.712.500; C17.800.827.610; C17.800.882.712.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
C562840	Breast Cancer, Familial (supp.)
C563456	Colorectal Cancer, Hereditary Nonpolyposis, Type 5 (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C536928	Turcot syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 25 oncogenic, 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
MSH2 Loss OR MLH1 Loss	Nivolumab	Cancer	Sensitivity/Response	CIViC B	EID11677
MLH1 METHYLATION	Oxaliplatin	Stomach Carcinoma	Resistance	CIViC B	EID1315

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1800734	EPM2AIP1, MLH1		0.00	0

CTD chemical–gene interactions

81 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Decitabine	increases expression, increases reaction, decreases expression, affects methylation, affects reaction (+4 more)	7
chromium hexavalent ion	decreases response to substance, increases reaction, decreases expression, affects activity, affects reaction (+4 more)	5
bisphenol A	decreases expression, increases expression, increases methylation, affects cotreatment	4
sodium arsenite	affects expression, decreases reaction, affects cotreatment, decreases expression, increases methylation (+1 more)	4
Cisplatin	affects localization, increases expression, increases response to substance	4
Ascorbic Acid	affects cotreatment, decreases response to substance, increases reaction, increases response to substance	3
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
Doxorubicin	increases expression, increases response to substance, affects phosphorylation, affects response to substance	3
Estradiol	affects reaction, decreases expression, affects cotreatment, increases expression, increases response to substance (+1 more)	3
Fluorouracil	affects response to substance, increases response to substance	3
Oxygen	affects binding, increases reaction, decreases expression, decreases reaction, increases methylation	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
methacrylaldehyde	affects cotreatment, affects expression, affects oxidation, decreases expression, increases abundance	2
epigallocatechin gallate	affects cotreatment, decreases expression, decreases methylation, increases expression	2
Temozolomide	affects response to substance, affects cotreatment, affects expression	2
Acetylcysteine	increases expression, affects expression, decreases reaction, affects cotreatment	2
Acrolein	affects oxidation, decreases expression, increases abundance, affects cotreatment, affects expression	2
Air Pollutants	affects cotreatment, affects expression, affects oxidation, increases abundance, decreases expression	2
Air Pollutants, Occupational	affects expression, increases abundance, increases expression, increases methylation	2
Arsenic	increases methylation, decreases expression	2
Ozone	affects cotreatment, affects expression, affects oxidation, decreases expression, increases abundance	2
Cyclosporine	increases expression	2
tert-Butylhydroperoxide	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
naringenin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, affects expression, affects oxidation, increases abundance	1

Cellosaurus cell lines

27 cell lines: 24 cancer cell line, 2 spontaneously immortalized cell line, 1 telomerase immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1G24	PA285	Cancer cell line	Sex unspecified
CVCL_2235	VCaP	Cancer cell line	Male
CVCL_5027	SNU-1544	Cancer cell line	Female
CVCL_5030	SNU-1746	Cancer cell line	Male
CVCL_5040	SNU-251	Cancer cell line	Female
CVCL_A0BX	VCaP-CR	Cancer cell line	Male
CVCL_A1BP	VCaP AR-V7/pHag	Cancer cell line	Male
CVCL_B1X8	Abcam HeLa MLH1 KO	Cancer cell line	Female
CVCL_B2NZ	Abcam A-549 MLH1 KO	Cancer cell line	Male
CVCL_B8KK	Abcam HCT 116 MLH1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

430 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer