MSH2

Summary

MSH2 (mutS homolog 2, HGNC:7325) is a protein-coding gene on chromosome 2p21-p16.3, encoding DNA mismatch repair protein Msh2 (P43246). 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).

This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4436 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Lynch syndrome (Definitive, ClinGen) — +10 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 8,370 total — 1914 pathogenic, 313 likely-pathogenic
• Phenotypes (HPO): 72
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000251

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7325
Approved symbol	MSH2
Name	mutS homolog 2
Location	2p21-p16.3
Locus type	gene with protein product
Status	Approved
Aliases	HNPCC, HNPCC1, MSH-2
Ensembl gene	ENSG00000095002
Ensembl biotype	protein_coding
OMIM	609309
Entrez	4436

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 20 protein_coding, 5 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000233146, ENST00000406134, ENST00000467323, ENST00000543555, ENST00000644092, ENST00000644900, ENST00000645339, ENST00000645506, ENST00000646415, ENST00000713854, ENST00000713860, ENST00000713861, ENST00000713867, ENST00000713919, ENST00000910408, ENST00000910409, ENST00000918100, ENST00000918101, ENST00000918102, ENST00000918103, ENST00000918104, ENST00000918105, ENST00000918106, ENST00000918107, ENST00000918108, ENST00000946816

RefSeq mRNA: 38 — MANE Select: NM_000251 NM_000251, NM_001258281, NM_001406631, NM_001406632, NM_001406633, NM_001406634, NM_001406635, NM_001406636, NM_001406637, NM_001406638, NM_001406639, NM_001406640, NM_001406641, NM_001406642, NM_001406643, NM_001406644, NM_001406645, NM_001406646, NM_001406647, NM_001406648, NM_001406649, NM_001406650, NM_001406651, NM_001406652, NM_001406653, NM_001406654, NM_001406655, NM_001406656, NM_001406657, NM_001406658, NM_001406659, NM_001406660, NM_001406661, NM_001406662, NM_001406666, NM_001406669, NM_001406672, NM_001406674

CCDS: CCDS1834, CCDS58709, CCDS92750

Canonical transcript exons

ENST00000233146 — 16 exons

Exon	Start	End
ENSE00001603119	47412414	47412560
ENSE00001645164	47410094	47410372
ENSE00002205909	47414269	47414418
ENSE00002435435	47480696	47480871
ENSE00002445155	47470965	47471062
ENSE00002447081	47429742	47429941
ENSE00002457696	47408401	47408555
ENSE00002464870	47475025	47475270
ENSE00002464921	47416296	47416429
ENSE00002469848	47445548	47445657
ENSE00002487660	47463031	47463154
ENSE00002489881	47476367	47476571
ENSE00002512620	47478272	47478519
ENSE00002528054	47466658	47466808
ENSE00004021629	47482779	47483223
ENSE00004021637	47403156	47403402

Expression profiles

Bgee: expression breadth ubiquitous, 278 present calls, max score 97.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.5090 / max 354.6034, expressed in 1700 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20160	18.4551	1688
20159	0.8221	490
20158	0.2318	107

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.56	gold quality
oocyte	CL:0000023	96.49	gold quality
ventricular zone	UBERON:0003053	95.74	gold quality
ganglionic eminence	UBERON:0004023	94.93	gold quality
embryo	UBERON:0000922	93.72	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.58	gold quality
cortical plate	UBERON:0005343	90.65	gold quality
pigmented layer of retina	UBERON:0001782	89.57	gold quality
retina	UBERON:0000966	89.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.28	gold quality
adrenal tissue	UBERON:0018303	88.63	gold quality
middle frontal gyrus	UBERON:0002702	86.86	gold quality
endometrium epithelium	UBERON:0004811	86.72	gold quality
Brodmann (1909) area 10	UBERON:0013541	86.63	gold quality
rectum	UBERON:0001052	86.17	gold quality
prefrontal cortex	UBERON:0000451	85.75	gold quality
cerebellar hemisphere	UBERON:0002245	84.90	gold quality
cerebellar cortex	UBERON:0002129	84.89	gold quality
calcaneal tendon	UBERON:0003701	84.71	gold quality
endometrium	UBERON:0001295	84.63	gold quality
vermiform appendix	UBERON:0001154	84.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.32	gold quality
right uterine tube	UBERON:0001302	84.29	gold quality
lymph node	UBERON:0000029	84.24	gold quality
bone marrow	UBERON:0002371	84.23	gold quality
cerebellum	UBERON:0002037	84.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.06	gold quality
corpus callosum	UBERON:0002336	83.99	gold quality
frontal pole	UBERON:0002795	83.83	gold quality
bronchial epithelial cell	CL:0002328	83.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.72
E-MTAB-7008	no	425.06
E-GEOD-124858	no	119.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, DNMT1, E2F4, HIF1A, JUN, MBD2, MYC, NF1, TP53

miRNA regulators (miRDB)

25 targeting MSH2, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-16-2-3P	99.29	70.60	1954
HSA-MIR-195-3P	99.29	70.61	1954
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-3973	99.20	69.19	1990
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-4724-3P	97.57	67.31	785
HSA-MIR-3909	97.55	66.78	887

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)
• Further characterization of the mutational spectrum of MSH2 gene in HNPCC families. (PMID:11748856)
• hMSH2-hMSH3 did not appear to bind any of the 8-oxo-G containing DNA substrates nor was there enhanced ATPase or ADP –> ATP exchange activities. (PMID:11756455)
• 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)
• interacts with MutY homolog (PMID:11801590)
• A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. (PMID:11809679)
• hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA (PMID:11809883)
• differential expression associated with prostate carcinoma recurrence (PMID:11857301)
• Large deletions have been detected in MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC). (PMID:11857745)
• Mutation analysis of MLH1 and MSH2 genes performed by denaturing high-performance liquid chromatography (PMID:11879922)
• expression changes during menstrual cycle in parallel with proliferative patients; expression in endometrial carcinoma consistent with PCNA expression (PMID:11920468)
• The expression rates of the hMSH2, hMLH1 and hPMS1 genes were found to differ among various types of malignant lymphoproliferative disorders of B-cell origin, with higher incidence of gene expression aberrations associated with aggressive disease. (PMID:11999575)
• Interactions between p53, hMSH2-hMSH6 and HMG I(Y) on Holliday junctions and bulged bases (PMID:12034830)
• Two mutations and four polymorphisms detected in Brazilian families with suspected Hereditary Nonpolyposis Colorectal Cancer (PMID:12095971)
• Missense mutation in hMSH2 results in reduced hMSH2-hMSH6 dimers affecting mismatch-dependent molecular switch function in HNPCC (PMID:12124176)
• A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. (PMID:12203789)
• Identification of transdominant-negative genetic suppressor elements derived from hMSH2 that mediate resistance to 6-thioguanine. (PMID:12391284)
• The founder mutation MSH2*1906G–>C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population (PMID:12454801)
• 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)
• Patients carry missense mutations in both MSH2 and MSH6. (PMID:12522549)
• Early onset brain tumor and lymphoma in MSH2-deficient children (PMID:12549480)
• in glioblastoma multiforme patients expression of Msh2 is not related to age (PMID:12582944)
• Although very rare in the population, MSH2*1906G>C is found at an increased frequency in young Jewish patients with colorectal cancer. (PMID:12595050)
• loss of MLH1 and MSH2 expression seen in approximately equal frequency in small intestine neoplasms with microsatellite instability (PMID:12627520)
• Positive relationship between the expression of hMSH2 mRNA and the differentiated types of gastric cancer. (PMID:12632492)
• We identified a common deletion in MSH2, accounting for approximately 10% of our cohort of clinically selected North American families with HNPCC Genealogical, molecular, and haplotype studies showed that this deletion represents a founder mutation (PMID:12658575)
• Germline mutation in MSH2 exon 1, codon 61, nucleotide 181, stopping translation noted in one Uraguayan HNPCC family; and in another mutation at exon 3: at nucleotide 530, codon 117, causing frameshift and premature stop codon eight base pairs later (PMID:12660027)
• Mutations of this protein show microsatellite instability in human prostatic cancer (PMID:12684669)
• Data show that alterations in global DNA methylation may influence tumor progression but are not directly associated with the inactivation of the mismatch-repair proteins hMLH1 and hMSH2. (PMID:12684691)
• A SNP [gIVS12-6T > C]in the MSH2 gene was found in 30 of 277 patients with lymphoma, leukemia & myelodysplasic syndromes. In lymphoma, the SNP frequency was 0.09, suggesting an association with the development of lymphomas. (PMID:12688322)
• results indicated that the disruption of the mismatch repair system of Msh2 does not mainly lead to allelic loss of the FHIT/FRA3B locus as well as microsatellite instability in esophageal cancer (PMID:12697969)
• Our findings indicate that reduced expression of the MMR proteins may have an important contribution in the development of a subset of TCCs and suggest a potential role for MMR expression as prognostic indicators. (PMID:12712438)
• msh2 expression was identified in recurrent glioblastoma multiforme (PMID:12754350)
• Germline missense mutations in the hMSH2 gene is associated with sporadic colorectal cancer (PMID:12792735)
• Although mutator pathway was implicated in younger-age-onset colorectal carcinogenesis, many tumors appeared to evolve from different genetic events other than hMSH2 and hMLH1 mutations frequently identified in nonpolyposis colorectal cancer (PMID:12808326)
• hMSH2-deficient tumor cell lines did not accurately repair plasmid DNA double-strand breaks by homologous recombination. MSH2-deficiency could promote mutation caused by gene conversion which may also contribute to cancer predisposition. (PMID:12810667)
• Ductal pancreatic carcinomas express hMLH2 protein irrespective of their differentiation (PMID:12817878)
• Four different MSH2 deletions (exons 1-2, exons 1-6, exons 1-7 and exon 8) have been found in Lynch syndrome patients. (PMID:12938096)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	msh2	ENSDARG00000018022
mus_musculus	Msh2	ENSMUSG00000024151
rattus_norvegicus	Msh2	ENSRNOG00000015796
drosophila_melanogaster	spel1	FBGN0015546
caenorhabditis_elegans	msh-2	WBGENE00003418

Paralogs (4): MSH4 (ENSG00000057468), MSH3 (ENSG00000113318), MSH6 (ENSG00000116062), MSH5 (ENSG00000204410)

Protein

Protein identifiers

DNA mismatch repair protein Msh2 — P43246 (reviewed: P43246)

Alternative names: MutS protein homolog 2

All UniProt accessions (12): P43246, A0A2R8Y6P0, A0A2R8Y713, A0A2R8Y7S8, A0A2R8YFH0, A0A2R8YG02, A0AAQ5BH31, A0AAQ5BH33, A0AAQ5BH41, A0AAQ5BH48, A0AAQ5BH55, E9PHA6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containing DNA strand. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP–>ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis.

Subunit / interactions. Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer consisting of MSH2-MSH6 (MutS alpha) or MSH2-MSH3 (MutS beta). Both heterodimers form a ternary complex with MutL alpha (MLH1-PMS1). Interacts with MCM9; the interaction recruits MCM9 to chromatin. Interacts with MCM8. Interacts with EXO1. 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 ATR. Interacts with SLX4/BTBD12; this interaction is direct and links MutS beta to SLX4, a subunit of different structure-specific endonucleases. Interacts with SMARCAD1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. Sequentially deacetylated and polyubiquitinated by HDAC6, leading to MSH2 degradation.

Disease relevance. Lynch syndrome 1 (LYNCH1) [MIM:120435] 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. 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. 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. Mismatch repair cancer syndrome 2 (MMRCS2) [MIM:619096] 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. 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 may be associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutS family.

Isoforms (2)

UniProt ID	Names	Canonical?
P43246-1	1	yes
P43246-2	2

RefSeq proteins (38): NP_000242, NP_001245210, NP_001393560, NP_001393561, NP_001393562, NP_001393563, NP_001393564, NP_001393565, NP_001393566, NP_001393567, NP_001393568, NP_001393569, NP_001393570, NP_001393571, NP_001393572, NP_001393573, NP_001393574, NP_001393575, NP_001393576, NP_001393577, NP_001393578, NP_001393579, NP_001393580, NP_001393581, NP_001393582, NP_001393583, NP_001393584, NP_001393585, NP_001393586, NP_001393587, NP_001393588, NP_001393589, NP_001393590, NP_001393591, NP_001393595, NP_001393598, NP_001393601, NP_001393603 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000432	DNA_mismatch_repair_MutS_C	Domain
IPR007695	DNA_mismatch_repair_MutS-lik_N	Domain
IPR007696	DNA_mismatch_repair_MutS_core	Domain
IPR007860	DNA_mmatch_repair_MutS_con_dom	Domain
IPR007861	DNA_mismatch_repair_MutS_clamp	Domain
IPR011184	DNA_mismatch_repair_Msh2	Family
IPR016151	DNA_mismatch_repair_MutS_N	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR032642	Msh2_ATP-bd	Domain
IPR036187	DNA_mismatch_repair_MutS_sf	Homologous_superfamily
IPR036678	MutS_con_dom_sf	Homologous_superfamily
IPR045076	MutS	Family

Pfam: PF00488, PF01624, PF05188, PF05190, PF05192

UniProt features (261 total): sequence variant 139, helix 43, strand 39, turn 15, modified residue 8, cross-link 5, mutagenesis site 5, sequence conflict 2, initiator methionine 1, chain 1, splice variant 1, region of interest 1, binding site 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
8RB1	X-RAY DIFFRACTION	2.08
8RAU	X-RAY DIFFRACTION	2.33
8RB2	X-RAY DIFFRACTION	2.53
8RAV	X-RAY DIFFRACTION	2.63
8RB0	X-RAY DIFFRACTION	2.67
8RAW	X-RAY DIFFRACTION	2.69
3THX	X-RAY DIFFRACTION	2.7
2O8B	X-RAY DIFFRACTION	2.75
8R7E	X-RAY DIFFRACTION	2.78
8AG6	ELECTRON MICROSCOPY	2.8
8R7C	X-RAY DIFFRACTION	2.82
8RAZ	X-RAY DIFFRACTION	2.84
3THY	X-RAY DIFFRACTION	2.89
2O8D	X-RAY DIFFRACTION	3
8RZ9	ELECTRON MICROSCOPY	3.02
8RZ8	ELECTRON MICROSCOPY	3.06
3THW	X-RAY DIFFRACTION	3.09
8OLX	ELECTRON MICROSCOPY	3.1
8OMQ	ELECTRON MICROSCOPY	3.11
8R7V	ELECTRON MICROSCOPY	3.12
8RAX	X-RAY DIFFRACTION	3.16
2O8F	X-RAY DIFFRACTION	3.25
8OMA	ELECTRON MICROSCOPY	3.29
2O8E	X-RAY DIFFRACTION	3.3
8OM9	ELECTRON MICROSCOPY	3.32
2O8C	X-RAY DIFFRACTION	3.37
8RZ7	ELECTRON MICROSCOPY	3.37
8OMO	ELECTRON MICROSCOPY	3.43
8OM5	ELECTRON MICROSCOPY	3.52
3THZ	X-RAY DIFFRACTION	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43246-F1	85.60	0.46

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 (1): 669–676

Post-translational modifications (13): 892, 921, 430, 845, 847, 871, 892, 2, 555, 567, 845, 847, 871

Mutagenesis-validated functional residues (5):

Position	Phenotype
675	no effect on mismatch binding, complete loss of dna repair function when associated with msh6 mutant r-1140.
845	reduces interaction with msh6. reduces acetylation; when associated with r-847, r-871 and r-892.
847	reduces interaction with msh6. reduces acetylation; when associated with r-845, r-871 and r-892.
871	does not affect interaction with msh6. reduces acetylation; when associated with r-845, r-847 and r-892.
892	does not affect interaction with msh6. reduces acetylation; when associated with r-845, r-847 and r-871.

Function

Pathways and Gene Ontology

Reactome pathways

15 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-5632927	Defective Mismatch Repair Associated With MSH3
R-HSA-5632928	Defective Mismatch Repair Associated With MSH2
R-HSA-5632968	Defective Mismatch Repair Associated With MSH6
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
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: 591 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GNF2_MSH2, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MORF_SMC1L1, TGCGCANK_UNKNOWN, E2F4DP1_01, GOBP_B_CELL_ACTIVATION, FISCHER_G1_S_CELL_CYCLE

GO Biological Process (28): in utero embryonic development (GO:0001701), somatic recombination of immunoglobulin genes involved in immune response (GO:0002204), oxidative phosphorylation (GO:0006119), DNA repair (GO:0006281), mismatch repair (GO:0006298), DNA damage tolerance (GO:0006301), double-strand break repair (GO:0006302), mitotic recombination (GO:0006312), germ cell development (GO:0007281), determination of adult lifespan (GO:0008340), male gonad development (GO:0008584), response to X-ray (GO:0010165), response to UV-B (GO:0010224), somatic hypermutation of immunoglobulin genes (GO:0016446), somatic recombination of immunoglobulin gene segments (GO:0016447), B cell mediated immunity (GO:0019724), B cell differentiation (GO:0030183), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), negative regulation of neuron apoptotic process (GO:0043524), maintenance of DNA repeat elements (GO:0043570), isotype switching (GO:0045190), negative regulation of DNA recombination (GO:0045910), positive regulation of isotype switching to IgA isotypes (GO:0048298), positive regulation of isotype switching to IgG isotypes (GO:0048304), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), regulation of cell cycle (GO:0051726)

GO Molecular Function (25): DNA binding (GO:0003677), chromatin binding (GO:0003682), damaged DNA binding (GO:0003684), ATP binding (GO:0005524), enzyme activator activity (GO:0008047), ATP-dependent activity, acting on DNA (GO:0008094), ATP hydrolysis activity (GO:0016887), centromeric DNA binding (GO:0019237), guanine/thymine mispair binding (GO:0032137), protein homodimerization activity (GO:0042803), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), magnesium ion binding (GO:0000287), four-way junction DNA binding (GO:0000400), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), protein binding (GO:0005515), mismatched DNA binding (GO:0030983), dinucleotide insertion or deletion binding (GO:0032139), single guanine insertion binding (GO:0032142), single thymine insertion binding (GO:0032143), dinucleotide repeat insertion binding (GO:0032181), oxidized purine DNA binding (GO:0032357), MutLalpha complex binding (GO:0032405), ADP binding (GO:0043531)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), MutSalpha complex (GO:0032301), MutSbeta complex (GO:0032302), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Diseases of Mismatch Repair (MMR)	3
Mismatch Repair	2
Transcriptional Regulation by TP53	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
DNA binding	3
DNA metabolic process	2
DNA damage response	2
DNA repair	2
somatic diversification of immunoglobulins	2
binding	2
ATP-dependent activity	2
cellular anatomical structure	2
mismatch repair complex	2
nuclear protein-containing complex	2
chordate embryonic development	1
somatic diversification of immunoglobulins involved in immune response	1
somatic recombination of immunoglobulin gene segments	1
aerobic respiration	1
proton motive force-driven ATP synthesis	1
DNA replication	1
DNA recombination	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
multicellular organismal process	1
gonad development	1
development of primary male sexual characteristics	1
response to ionizing radiation	1
response to UV	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immune receptors via germline recombination within a single locus	1
lymphocyte mediated immunity	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
lymphocyte differentiation	1
B cell activation	1
mitotic S phase	1
mitotic DNA damage checkpoint signaling	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
nucleic acid binding	1

Protein interactions and networks

STRING

3824 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSH2	MLH1	P40692	999
MSH2	PMS1	P54277	999
MSH2	PMS2	P54278	999
MSH2	MLH3	P49751	997
MSH2	EXO1	Q9UQ84	996
MSH2	ATM	Q13315	995
MSH2	MSH3	P20585	992
MSH2	MSH6	P52701	992
MSH2	ARID1A	O14497	970
MSH2	BRCA1	P38398	947
MSH2	BRCA2	P51587	926
MSH2	EPCAM	P16422	912
MSH2	SLX4	Q8IY92	900
MSH2	RAD51	Q06609	893
MSH2	MUTYH	Q9UIF7	892

IntAct

217 interactions, top by confidence:

A	B	Type	Score
MSH2	MSH3	psi-mi:“MI:0915”(physical association)	0.920
MSH3	MSH2	psi-mi:“MI:0915”(physical association)	0.920
MSH2	MSH3	psi-mi:“MI:0407”(direct interaction)	0.920
MSH2	MSH3	psi-mi:“MI:0914”(association)	0.920
MSH2	MSH6	psi-mi:“MI:0915”(physical association)	0.910
MSH2	MSH6	psi-mi:“MI:0407”(direct interaction)	0.910
MSH6	MSH2	psi-mi:“MI:2364”(proximity)	0.910
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MSH2	MCM9	psi-mi:“MI:0914”(association)	0.690
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
SLX4	MSH2	psi-mi:“MI:0915”(physical association)	0.570
SLX4	MSH2	psi-mi:“MI:0914”(association)	0.570

BioGRID (496): MSH2 (Affinity Capture-MS), MSH2 (Reconstituted Complex), MSH2 (Affinity Capture-MS), ANXA6 (Co-fractionation), DNAJC9 (Co-fractionation), EIF3B (Co-fractionation), FEN1 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation), MSH2 (Co-fractionation)

ESM2 similar proteins: A0JN39, A1C4A5, A1DBH2, A2R5J1, B0Y9Q4, D2SW95, F1QGH9, O13396, O24617, P21271, P23514, P33121, P35249, P43246, P43247, P46735, P53041, P53042, P53618, P54275, P70569, Q00647, Q05096, Q06364, Q0CEX5, Q0DBU5, Q13616, Q1DLP2, Q2U919, Q2US45, Q3MHE4, Q4WC55, Q5R4A0, Q5R4G6, Q5R922, Q5XXB5, Q5ZIA5, Q60676, Q66HV4, Q7ZVX6

Diamond homologs: A0AHX3, A1CDD4, A1DCB2, A2R1F6, A3CKV4, A3DDI3, A3LU10, A4IRL1, A5DEV6, A5DYV8, A5IS30, A6QG46, A6R7S1, A6RPB6, A6U0W1, A6ZTR3, A7EC69, A7GTK1, A7TTQ1, A7X169, A7Z7E7, A8AUW9, A8Z1S5, A9KR74, B0S1P2, B0YCF6, B1I9K1, B2ILV2, B2TS45, B2V583, B5E7E8, B8D298, B8DI00, B8ZLH4, B9K937, C1C5E4, C1CCH3, C1CIQ8, C1CPR7, C1L2D7

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MSH2	up-regulates	BLM	binding
MSH2	“form complex”	MSH2/MSH6	binding
MSH2	“up-regulates activity”	DNA_repair

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
G1/S Transition	5	10.3×	7e-03
PKR-mediated signaling	7	8.7×	2e-03
Signaling by ALK fusions and activated point mutants	6	8.0×	7e-03
Regulation of PD-L1(CD274) transcription	7	6.7×	6e-03
Interleukin-4 and Interleukin-13 signaling	7	6.4×	7e-03
Signaling by Interleukins	10	5.7×	2e-03
Cell Cycle, Mitotic	11	4.7×	2e-03
Diseases of signal transduction by growth factor receptors and second messengers	9	4.5×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
mismatch repair	6	27.8×	3e-05
negative regulation of innate immune response	5	18.2×	1e-03
cellular response to UV	8	16.9×	3e-05
ribosomal large subunit biogenesis	5	15.8×	2e-03
intrinsic apoptotic signaling pathway	5	12.8×	4e-03
positive regulation of miRNA transcription	5	10.4×	9e-03
protein import into nucleus	9	9.3×	2e-04
negative regulation of cell growth	7	7.2×	5e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

8370 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1914
Likely pathogenic	313
Uncertain significance	2300
Likely benign	1395
Benign	234

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048814	NM_000251.3(MSH2):c.459del (p.Ala154fs)	Pathogenic
1048820	NM_000251.3(MSH2):c.-4_211+864del	Pathogenic
1048904	NM_000251.3(MSH2):c.646-1_792+486del	Pathogenic
1048971	NM_000251.3(MSH2):c.1662-2_1759+1del	Pathogenic
1049201	NM_000251.3(MSH2):c.1277-2_1386+1del	Pathogenic
1049214	NM_000251.3(MSH2):c.1760-3_2006-300del	Pathogenic
1049241	NM_000251.3(MSH2):c.212-1_366+712del	Pathogenic
1049338	NM_000251.3(MSH2):c.212-4_363del	Pathogenic
1049344	NM_000251.3(MSH2):c.2006-2_2210+1del	Pathogenic
1049439	NM_000251.3(MSH2):c.1387-5_1510+1293del	Pathogenic
1049506	NM_000251.3(MSH2):c.2280del (p.Phe760fs)	Pathogenic
1049573	NM_000251.3(MSH2):c.367-2_645+432del	Pathogenic
1049723	NM_000251.3(MSH2):c.266del (p.Val89fs)	Pathogenic
1049817	NM_000251.3(MSH2):c.965del (p.Gly322fs)	Pathogenic
1049937	NM_000251.3(MSH2):c.367-2_645+742del	Pathogenic
1050000	NM_000251.3(MSH2):c.2444del (p.Tyr815fs)	Pathogenic
1050002	NM_000251.3(MSH2):c.-2_211+156del	Pathogenic
1050018	NM_000251.3(MSH2):c.943-2_1076+1del	Pathogenic
1050033	NM_000251.3(MSH2):c.212-2_366+1del	Pathogenic
1050099	NM_000251.3(MSH2):c.-2_211+1del	Pathogenic
1050128	NM_000251.3(MSH2):c.367-2_645+1del	Pathogenic
1050167	NM_000251.3(MSH2):c.-1_212-2403del	Pathogenic
1050259	NM_000251.3(MSH2):c.1_211+1068del	Pathogenic
1050345	NM_000251.3(MSH2):c.645+1G>C	Pathogenic
1050428	NM_000251.3(MSH2):c.1077-2_1276+1del	Pathogenic
1050439	NM_000251.3(MSH2):c.2635-3_2805del	Pathogenic
1050577	NM_000251.3(MSH2):c.1662-1_1759+1048del	Pathogenic
1050607	NM_000251.3(MSH2):c.367-3_645+631del	Pathogenic
1050647	NM_000251.3(MSH2):c.793-2_943-14del	Pathogenic
1050723	NM_000251.3(MSH2):c.999dup (p.Lys334Ter)	Pathogenic

SpliceAI

2962 predictions. Top by Δscore:

Variant	Effect	Δscore
2:47403357:G:GT	donor_gain	1.0000
2:47403357:G:T	donor_gain	1.0000
2:47403375:G:GT	donor_gain	1.0000
2:47403379:TGATC:T	donor_gain	1.0000
2:47403400:C:T	donor_gain	1.0000
2:47403400:CAGG:C	donor_loss	1.0000
2:47403402:GG:G	donor_loss	1.0000
2:47403403:G:GC	donor_loss	1.0000
2:47407923:T:G	donor_gain	1.0000
2:47408398:AAG:A	acceptor_gain	1.0000
2:47408399:A:G	acceptor_gain	1.0000
2:47408551:ATAAG:A	donor_loss	1.0000
2:47408554:AGGTA:A	donor_loss	1.0000
2:47408555:GGTA:G	donor_loss	1.0000
2:47408556:G:GA	donor_loss	1.0000
2:47408557:T:G	donor_loss	1.0000
2:47410092:A:AG	acceptor_gain	1.0000
2:47410093:G:GG	acceptor_gain	1.0000
2:47410368:GACAG:G	donor_gain	1.0000
2:47410373:G:GC	donor_loss	1.0000
2:47410373:G:GG	donor_gain	1.0000
2:47410374:T:A	donor_loss	1.0000
2:47412407:A:AG	acceptor_gain	1.0000
2:47412408:A:G	acceptor_gain	1.0000
2:47412412:A:AG	acceptor_gain	1.0000
2:47412413:G:GG	acceptor_gain	1.0000
2:47412413:GAT:G	acceptor_gain	1.0000
2:47412413:GATA:G	acceptor_gain	1.0000
2:47412413:GATAA:G	acceptor_gain	1.0000
2:47412559:AG:A	donor_loss	1.0000

AlphaMissense

6175 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:47466718:G:C	R524P	1.000
2:47476374:T:A	N671K	1.000
2:47476374:T:G	N671K	1.000
2:47476529:C:A	S723Y	1.000
2:47476534:T:C	F725L	1.000
2:47476535:T:C	F725S	1.000
2:47476536:C:A	F725L	1.000
2:47476536:C:G	F725L	1.000
2:47476545:A:C	E728D	1.000
2:47476545:A:T	E728D	1.000
2:47478303:G:C	D748H	1.000
2:47478304:A:C	D748A	1.000
2:47478304:A:G	D748G	1.000
2:47478304:A:T	D748V	1.000
2:47478305:T:A	D748E	1.000
2:47478305:T:G	D748E	1.000
2:47478306:G:A	E749K	1.000
2:47478307:A:C	E749A	1.000
2:47478307:A:G	E749G	1.000
2:47478307:A:T	E749V	1.000
2:47478308:A:C	E749D	1.000
2:47478308:A:T	E749D	1.000
2:47478312:G:A	G751R	1.000
2:47478312:G:C	G751R	1.000
2:47478313:G:A	G751E	1.000
2:47478316:G:C	R752T	1.000
2:47478316:G:T	R752I	1.000
2:47478317:A:C	R752S	1.000
2:47478317:A:T	R752S	1.000
2:47478318:G:A	G753R	1.000

dbSNP variants (sampled 300 via entrez): RS1000006941 (2:47556865 G>A,C), RS1000013184 (2:47560331 C>T), RS1000074419 (2:47586351 T>C,G), RS1000079427 (2:47529126 A>G), RS1000081125 (2:47560716 A>C), RS1000084255 (2:47424666 G>T), RS1000090311 (2:47454794 C>T), RS1000099648 (2:47551602 C>G), RS1000112260 (2:47618186 C>A,G,T), RS1000115859 (2:47507114 T>C), RS1000131420 (2:47522368 T>C), RS1000136792 (2:47626085 A>T), RS1000140843 (2:47497424 G>C), RS1000164382 (2:47573648 C>G), RS1000175436 (2:47460027 G>A,C)

Disease associations

OMIM: gene MIM:609309 | disease phenotypes: MIM:120435, MIM:158320, MIM:619096, MIM:276300, MIM:613659, MIM:114480, MIM:604370, MIM:167000, MIM:114500, MIM:614337, MIM:208900, MIM:609310

GenCC curated gene-disease

Disease	Classification	Inheritance
Lynch syndrome 1	Definitive	Autosomal dominant
Lynch syndrome	Definitive	Autosomal dominant
mismatch repair cancer syndrome 1	Definitive	Autosomal recessive
mismatch repair cancer syndrome 2	Definitive	Autosomal recessive
ovarian cancer	Strong	Autosomal dominant
Muir-Torre syndrome	Strong	Autosomal dominant
prostate cancer	Moderate	Autosomal dominant
rhabdomyosarcoma	Moderate	Autosomal recessive
malignant pancreatic neoplasm	Moderate	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 (41): hereditary neoplastic syndrome (MONDO:0015356), Lynch syndrome 1 (MONDO:0007356), Lynch syndrome (MONDO:0005835), hereditary breast ovarian cancer syndrome (MONDO:0003582), Muir-Torre syndrome (MONDO:0008018), mismatch repair cancer syndrome 2 (MONDO:0030840), breast cancer (MONDO:0007254), colon carcinoma (MONDO:0002032), endometrial carcinoma (MONDO:0002447), bile duct cancer (MONDO:0003059), hereditary nonpolyposis colon cancer (MONDO:0018630), mismatch repair cancer syndrome 1 (MONDO:0010159), gastric cancer (MONDO:0001056), hereditary breast carcinoma (MONDO:0016419), invasive ductal breast carcinoma (MONDO:0004953)

Orphanet (16): Inherited cancer-predisposing syndrome (Orphanet:140162), Lynch syndrome (Orphanet:144), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Muir-Torre syndrome (Orphanet:587), Hereditary nonpolyposis colon cancer (Orphanet:443909), Constitutional mismatch repair deficiency syndrome (Orphanet:252202), Hereditary breast cancer (Orphanet:227535), Rare ovarian cancer (Orphanet:213500), Intestinal polyposis syndrome (Orphanet:104010), Ependymoma (Orphanet:251636), Glioblastoma (Orphanet:360), Ataxia-telangiectasia (Orphanet:100), Hereditary papillary renal cell carcinoma (Orphanet:47044), Rhabdomyosarcoma (Orphanet:780), Hepatoblastoma (Orphanet:449)

HPO phenotypes

72 total (30 of 72 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:0001123	Visual field defect
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001260	Dysarthria
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: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
HP:0002354	Memory impairment
HP:0002376	Developmental regression
HP:0002516	Increased intracranial pressure
HP:0002671	Basal cell carcinoma

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002709_13	Electroencephalogram traits	7.000000e-06
GCST003264_267	Post bronchodilator FEV1/FVC ratio	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0006870	alpha wave measurement
EFO:0004713	FEV/FVC ratio

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D001260	Ataxia Telangiectasia	C10.228.140.252.190.530.060; C10.562.100; C10.597.350.090.500.530.060; C14.907.823.213; C16.320.080; C16.320.798.250; C18.452.284.060; C20.673.795.250
D003111	Colonic Polyps	C23.300.825.411.235
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D005909	Glioblastoma	C04.557.465.625.600.380.080.335; C04.557.470.670.380.080.335; C04.557.580.625.600.380.080.335
D018197	Hepatoblastoma	C04.557.435.380
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
D010048	Ovarian Cysts	C04.182.612; C12.050.351.500.056.630.580; C12.100.250.056.630.580; C19.391.630.580
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
D012004	Rectal Neoplasms	C04.588.274.476.411.307.790; C06.301.371.411.307.790; C06.405.249.411.307.790; C06.405.469.491.307.790; C06.405.469.860.180.500
D012208	Rhabdomyosarcoma	C04.557.450.590.550.660; C04.557.450.795.550.660
D012509	Sarcoma	C04.557.450.795
C562840	Breast Cancer, Familial (supp.)
C563971	Colorectal Cancer, Hereditary Nonpolyposis, Type 4 (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C536928	Turcot syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296019 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items; also 5 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
MSH2 Loss OR MLH1 Loss	Nivolumab	Cancer	Sensitivity/Response	CIViC B	EID11677
MSH2 Loss	Anti-PD-1 Monoclonal Antibody MEDI0680 + Durvalumab	Transitional Cell Carcinoma	Sensitivity/Response	CIViC C	EID1877

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4638843	MSH2		0.00	0
rs1863332	MSH2		0.00	0

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.28	Kd	52.92	nM	CHEMBL5653589
7.28	ED50	52.92	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 10 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148784: Binding affinity to human MSH2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0529	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases reaction, affects reaction, decreases expression, affects cotreatment, increases activity (+2 more)	8
sodium arsenite	affects expression, decreases reaction, affects cotreatment, decreases expression, increases abundance (+1 more)	7
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, affects response to substance	5
bisphenol A	increases expression, affects expression, decreases expression, decreases methylation, affects cotreatment	4
Arsenic	increases methylation, decreases expression, increases abundance, affects expression	4
Cisplatin	affects binding, affects localization, increases reaction, decreases expression, increases expression (+3 more)	4
Hydrogen Peroxide	increases expression, decreases reaction, decreases response to substance, affects expression, affects cotreatment	4
Aflatoxin B1	affects expression, increases expression	4
Temozolomide	affects cotreatment, affects expression, affects response to substance, decreases response to substance	3
Decitabine	decreases expression, decreases reaction, decreases methylation, increases expression	3
Doxorubicin	decreases expression, increases expression, increases response to substance	3
Fluorouracil	decreases expression, affects response to substance	3
lasiocarpine	decreases expression, increases metabolic processing	2
chromium hexavalent ion	increases reaction, increases response to substance, affects cotreatment	2
Irinotecan	decreases expression, affects response to substance	2
Acetaminophen	increases expression, decreases reaction	2
Acetylcysteine	affects reaction, decreases expression, decreases reaction, increases expression, affects expression	2
Ascorbic Acid	increases reaction, increases response to substance, affects cotreatment	2
Copper	affects binding, decreases expression	2
Estradiol	decreases expression, increases expression, increases response to substance	2
Oxygen	decreases expression	2
Quercetin	decreases expression, increases expression	2
Valproic Acid	increases expression, decreases expression	2
Cyclosporine	decreases expression	2
Vitamin K 3	decreases reaction, decreases response to substance, affects expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
pradimicin-IRD	decreases expression	1
dicrotophos	decreases expression	1
naringenin	affects cotreatment, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118749	Binding	Binding affinity to MSH2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

454 cell lines: 446 cancer cell line, 5 telomerase immortalized cell line, 2 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0065	Jurkat	Cancer cell line	Male
CVCL_0354	J.CaM1.6	Cancer cell line	Male
CVCL_0367	Jurkat E6.1	Cancer cell line	Male
CVCL_0584	Jurkat Wurzburg	Cancer cell line	Male
CVCL_0D86	JPX-9	Cancer cell line	Male
CVCL_1061	Jurkat clone A3	Cancer cell line	Male
CVCL_1316	J.RT3-T3.5	Cancer cell line	Male
CVCL_1326	Karpas-45	Cancer cell line	Male
CVCL_1E01	JLTRG	Cancer cell line	Male
CVCL_1E02	JLTRG-R5	Cancer cell line	Male

Clinical trials (associated diseases)

468 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