MSH6

Summary

MSH6 (mutS homolog 6, HGNC:7329) is a protein-coding gene on chromosome 2p16.3, encoding DNA mismatch repair protein Msh6 (P52701). Component of the post-replicative DNA mismatch repair system (MMR). In precision oncology, MSH6 LOSS confers sensitivity to Anti-PD-1 Monoclonal Antibody MEDI0680 + Durvalumab in Transitional Cell Carcinoma (CIViC Level C). It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described.

Source: NCBI Gene 2956 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mismatch repair cancer syndrome 1 (Definitive, ClinGen) — +10 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 10,375 total — 1792 pathogenic, 217 likely-pathogenic
• Phenotypes (HPO): 74
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000179

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7329
Approved symbol	MSH6
Name	mutS homolog 6
Location	2p16.3
Locus type	gene with protein product
Status	Approved
Aliases	MSH-6
Ensembl gene	ENSG00000116062
Ensembl biotype	protein_coding
OMIM	600678
Entrez	2956

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 18 protein_coding, 8 retained_intron, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000234420, ENST00000411819, ENST00000420813, ENST00000445503, ENST00000454137, ENST00000455383, ENST00000456246, ENST00000493177, ENST00000540021, ENST00000607272, ENST00000652107, ENST00000673637, ENST00000673922, ENST00000699999, ENST00000700000, ENST00000700001, ENST00000700002, ENST00000700003, ENST00000700004, ENST00000700005, ENST00000700006, ENST00000700007, ENST00000700008, ENST00000700009, ENST00000700010, ENST00000700011, ENST00000895687, ENST00000895688, ENST00000895689, ENST00000895690, ENST00000936508, ENST00000936509, ENST00000936510, ENST00000936511

RefSeq mRNA: 42 — MANE Select: NM_000179 NM_000179, NM_001281492, NM_001281493, NM_001281494, NM_001406795, NM_001406796, NM_001406797, NM_001406798, NM_001406799, NM_001406800, NM_001406801, NM_001406802, NM_001406803, NM_001406804, NM_001406805, NM_001406806, NM_001406807, NM_001406808, NM_001406809, NM_001406811, NM_001406812, NM_001406813, NM_001406814, NM_001406815, NM_001406816, NM_001406817, NM_001406818, NM_001406819, NM_001406820, NM_001406821, NM_001406822, NM_001406823, NM_001406824, NM_001406825, NM_001406826, NM_001406827, NM_001406828, NM_001406829, NM_001406830, NM_001406831, NM_001406832, NM_001407362

CCDS: CCDS1836, CCDS62906

Canonical transcript exons

ENST00000234420 — 10 exons

Exon	Start	End
ENSE00003523149	47798611	47801155
ENSE00003536910	47806204	47806358
ENSE00003549889	47795894	47796063
ENSE00003575195	47806779	47806953
ENSE00003601549	47804910	47805027
ENSE00003606429	47803420	47803685
ENSE00003628814	47790927	47791123
ENSE00003670482	47806452	47806651
ENSE00003677325	47805618	47805707
ENSE00003897270	47783145	47783493

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.7291 / max 566.0642, expressed in 1816 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20165	35.8801	1811
20166	9.8253	1680
20170	0.9397	365
20164	0.0645	37
202186	0.0110	5
20163	0.0086	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.75	gold quality
embryo	UBERON:0000922	96.83	gold quality
ganglionic eminence	UBERON:0004023	96.43	gold quality
adrenal tissue	UBERON:0018303	96.29	gold quality
secondary oocyte	CL:0000655	95.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.82	gold quality
ovary	UBERON:0000992	93.36	gold quality
tendon of biceps brachii	UBERON:0008188	92.79	gold quality
left ovary	UBERON:0002119	92.65	gold quality
cortical plate	UBERON:0005343	92.64	gold quality
cartilage tissue	UBERON:0002418	92.60	gold quality
calcaneal tendon	UBERON:0003701	92.14	gold quality
right ovary	UBERON:0002118	91.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.96	gold quality
tendon	UBERON:0000043	91.55	gold quality
male germ cell	CL:0000015	91.47	gold quality
cauda epididymis	UBERON:0004360	91.35	gold quality
sperm	CL:0000019	91.25	gold quality
islet of Langerhans	UBERON:0000006	91.22	gold quality
germinal epithelium of ovary	UBERON:0001304	90.99	gold quality
tibia	UBERON:0000979	90.96	gold quality
trabecular bone tissue	UBERON:0002483	90.90	gold quality
colonic epithelium	UBERON:0000397	90.80	gold quality
smooth muscle tissue	UBERON:0001135	90.58	gold quality
tonsil	UBERON:0002372	90.57	gold quality
endothelial cell	CL:0000115	90.38	gold quality
corpus callosum	UBERON:0002336	90.35	gold quality
testis	UBERON:0000473	90.17	gold quality
bone marrow cell	CL:0002092	90.09	gold quality
sural nerve	UBERON:0015488	89.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, KAT7, NCOA1, NCOA2, NCOA3, SP1, SP3

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• germline mutations in atypical HNPCC (PMID:11333868)
• mutations in sporadic endometrial adenocarcinoma (PMID:11474654)
• mutational analysis in HNPCC (PMID:11524701)
• clinical characteristics/phenotypes of patients with germline mutations (PMID:11709755)
• hMSH2-hMSH6 is activated by recognition of 8-oxo-G lesions. Our data are consistent with the notion that post-replication MMR only participates in the repair of mismatched 8-oxo-G lesions (PMID:11756455)
• interacts with MutY homolog (PMID:11801590)
• Germline mutations in MSH6 gene may be involved in the development of hereditary and sporadic colorectal cancer (PMID:11807791)
• hMutSalpha forms an ATP-dependent complex with hMutLalpha and hMutLbeta on DNA (PMID:11809883)
• how MSH6 mutations cause susceptibility to hereditary non-polyposis colorectal cancer syndrome (PMID:12019211)
• Interactions between p53, hMSH2-hMSH6 and HMG I(Y) on Holliday junctions and bulged bases (PMID:12034830)
• Patients carry missense mutations in both MSH2 and MSH6. (PMID:12522549)
• Oxidative stress in rheumatoid arthritis synovial tissue relaxes the mismatch repair system by suppressing MSH6, not only creating DNA adducts that are potentially mutagenic, but also suppressing the mechanisms that limit the DNA damage. (PMID:12574395)
• This protein is mutated in endometrial cancers. (PMID:12732731)
• Although genomic rearrangements of MSH6 play a small role in the spectrum of all mutations predisposing to hereditary non-polyposis colorectal cancer (HNPCC), up to 10-20% of patients with MSH6 negative tumors harbor germline rearrangements in this gene. (PMID:12920072)
• hMSH6, a component of the heterodimeric mismatch recognition complex hMSH2/hMSH6 (hMutS(alpha)), interacts with the BLM protein both in vivo and in vitro (PMID:12974384)
• MSH2/MSH6 complex binds specificity to DNA containing an IdUrd-G mismatch. (PMID:14500385)
• Altogether, our results indicate that disease-causing germline mutations of MSH6 are rare in HNPCC (PMID:14520694)
• characterized the structure of the MSH6 promoter region to examine the mechanisms of transcriptional regulation of the MSH6 gene (PMID:14585961)
• mutations in the MSH6 gene, and not in the POLD1 gene, are primarily responsible for the elevated HPRT mutation rates in a colon cancer cell line (PMID:14767555)
• Mutations of the MSH6 is associated with double primary cancers of the colorectum and the endometrium (PMID:14961575)
• Eight novel germline mutations in MSH6 familial and nonfamilial colorectal cancer patiens with loss of MSH6 function. (PMID:14974087)
• Data suggest that in human cell lines, ubiquitin-proteasome could play an important role in the regulation of hMutSalpha (hMSH2/hMSH6) protein expression, thereby regulating mismatch repair activity. (PMID:15043999)
• hMSH2/6 formed a complex with BLM-p53-RAD51 in response to the damaged DNA forks during double-stranded break repair. (PMID:15064730)
• MSH6 germline mutations are associated with increased cancer risk (PMID:15098177)
• MutSalpha has two nucleotide binding sites with differential specificities for ADP and ATP and the ADP.MutSalpha.ATP ternary complex has an important role in mismatch repair (PMID:15105434)
• role in sperm function, may have application in the development of a contraceptive vaccine (PMID:15274658)
• 1 new mutation (c.3488A>T) was found in a Korean HNPCC family. (PMID:15365995)
• A novel MSH6 germ-line mutation in hereditary nonpolyposis colorectal cancer has been identified. (PMID:15571801)
• Our results suggest that MSH6 may not be the underlying gene in breast cancer families with a history of colorectal and/or endometrial cancer. The Glu995STOP founder mutation is not a familial breast cancer predisposition allele. (PMID:15805151)
• Results indicate that protein kinase C (PKC) zeta modulates hMutS alpha (MSH2, MSH6)stability and protein levels, and suggest a role for PKC zeta in genome stability by regulating mismatch repair activity. (PMID:15808853)
• Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer. (PMID:15855819)
• This study investigates microsatellite instability in multiple primary colorectal cancers, and the relevance of MLH1, MSH2, and MSH6 gene expression in hereditary nonpolyposis colon cancer. (PMID:16106253)
• two MSH6 mutations may have a role in HNPCC-associated tumors (PMID:16418736)
• The inactivation of the DNA-mismatch-repair-gene MSH6 and microsatellite instability may play a minor role in somatic colorectal cancer development. (PMID:16902769)
• MSH6/MUTYH heterozygote mutation carriers display a predominant HNPCC molecular tumour phenotype, with microsatellite instability and underrepresentation of G>T transversions. (PMID:17039270)
• Bcl2 suppression of MMR may occur in a novel mechanism by directly regulating the heterodimeric hMSH2-hMSH6 complex, which potentially contributes to genetic instability and carcinogenesis (PMID:17259174)
• Two to six percent of CRC are caused by germline mutation in the mismatch repair genes MLH1, MSH2 and MSH6. (PMID:17454882)
• Expression of hMSH2 and hMLH1 proteins was up-regulated in three cases, whereas in two cases that of hPMS2 was increased. hMSH6 expression was comparable to that of normal cells in all cases. (PMID:17493242)
• genomic rearrangements of MLH1 and MSH6 in patients suspected of hereditary nonpolyposis colorectal cancer were studied using a new interphase FISH technique (PMID:17498565)
• heterozygous mutations in the MSH6 gene cause DNA mismatch repair (PMID:17557300)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	msh6	ENSDARG00000104541
mus_musculus	Msh6	ENSMUSG00000005370
rattus_norvegicus	Msh6	ENSRNOG00000016134
drosophila_melanogaster	Msh6	FBGN0036486
caenorhabditis_elegans	msh-6	WBGENE00003422

Paralogs (4): MSH4 (ENSG00000057468), MSH2 (ENSG00000095002), MSH3 (ENSG00000113318), MSH5 (ENSG00000204410)

Protein

Protein identifiers

DNA mismatch repair protein Msh6 — P52701 (reviewed: P52701)

Alternative names: G/T mismatch-binding protein, MutS protein homolog 6, MutS-alpha 160 kDa subunit

All UniProt accessions (8): P52701, A0A494C0M1, A0A8V8TPJ4, A0A8V8TPR2, A0A8V8TQJ0, A0A8V8TQW9, F8W7G9, F8WAX8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, 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. 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. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated ‘Lys-36’ of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction.

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). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with MCM9. 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. (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. The N-terminus is blocked. Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway.

Disease relevance. Lynch syndrome 5 (LYNCH5) [MIM:614350] 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. 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 3 (MMRCS3) [MIM:619097] 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 is associated with variants affecting the gene represented in this entry.

Domain organisation. The PWWP domain specifically recognizes and binds trimethylated ‘Lys-36’ of histone H3 (H3K36me3).

Similarity. Belongs to the DNA mismatch repair MutS family.

Isoforms (4)

UniProt ID	Names	Canonical?
P52701-1	GTBP-N	yes
P52701-2	GTBP-alt
P52701-3	3
P52701-4	4

RefSeq proteins (42): NP_000170, NP_001268421, NP_001268422, NP_001268423, NP_001393724, NP_001393725, NP_001393726, NP_001393727, NP_001393728, NP_001393729, NP_001393730, NP_001393731, NP_001393732, NP_001393733, NP_001393734, NP_001393735, NP_001393736, NP_001393737, NP_001393738, NP_001393740, NP_001393741, NP_001393742, NP_001393743, NP_001393744, NP_001393745, NP_001393746, NP_001393747, NP_001393748, NP_001393749, NP_001393750, NP_001393751, NP_001393752, NP_001393753, NP_001393754, NP_001393755, NP_001393756, NP_001393757, NP_001393758, NP_001393759, NP_001393760, NP_001393761, NP_001394291 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000313	PWWP_dom	Domain
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
IPR016151	DNA_mismatch_repair_MutS_N	Homologous_superfamily
IPR017261	DNA_mismatch_repair_MutS/MSH	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036187	DNA_mismatch_repair_MutS_sf	Homologous_superfamily
IPR036678	MutS_con_dom_sf	Homologous_superfamily
IPR045076	MutS	Family

Pfam: PF00488, PF00855, PF01624, PF05188, PF05190, PF05192

UniProt features (229 total): sequence variant 72, strand 47, helix 46, modified residue 25, turn 18, compositionally biased region 6, splice variant 4, mutagenesis site 3, sequence conflict 3, region of interest 2, chain 1, domain 1, binding site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
6OQM	X-RAY DIFFRACTION	2.2
2O8B	X-RAY DIFFRACTION	2.75
8AG6	ELECTRON MICROSCOPY	2.8
2O8D	X-RAY DIFFRACTION	3
2O8F	X-RAY DIFFRACTION	3.25
2O8E	X-RAY DIFFRACTION	3.3
2O8C	X-RAY DIFFRACTION	3.37
2GFU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52701-F1	77.93	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): 1134–1141

Post-translational modifications (25): 14, 41, 43, 70, 79, 91, 137, 200, 219, 227, 252, 254, 256, 261, 269, 274, 275, 279, 280, 309 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
103	abolishes binding to h3k36me3 and dna mismatch repair activity.
105–106	abolishes binding to h3k36me3 and dna mismatch repair activity.
1140	no effect on mismatch binding, complete loss of dna repair function when associated with msh2 mutant r-675.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5632928	Defective Mismatch Repair Associated With MSH2
R-HSA-5632968	Defective Mismatch Repair Associated With MSH6
R-HSA-1643685	Disease
R-HSA-5358508	Mismatch Repair
R-HSA-5423599	Diseases of Mismatch Repair (MMR)
R-HSA-73894	DNA Repair
R-HSA-9675135	Diseases of DNA repair

MSigDB gene sets: 440 (showing top): GOBP_CHROMOSOME_ORGANIZATION, MODULE_52, GOBP_REGULATION_OF_DNA_RECOMBINATION, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GNF2_MSH2, MORF_SMC1L1, YAGI_AML_WITH_INV_16_TRANSLOCATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_B_CELL_ACTIVATION, FISCHER_G1_S_CELL_CYCLE, MATTIOLI_MGUS_VS_PCL, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

GO Biological Process (15): meiotic mismatch repair (GO:0000710), DNA repair (GO:0006281), mismatch repair (GO:0006298), spermatogenesis (GO:0007283), determination of adult lifespan (GO:0008340), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), response to UV (GO:0009411), somatic hypermutation of immunoglobulin genes (GO:0016446), somatic recombination of immunoglobulin gene segments (GO:0016447), isotype switching (GO:0045190), negative regulation of DNA recombination (GO:0045910), intrinsic apoptotic signaling pathway (GO:0097193), chromatin organization (GO:0006325), DNA damage response (GO:0006974), negative regulation of DNA metabolic process (GO:0051053)

GO Molecular Function (20): chromatin binding (GO:0003682), damaged DNA binding (GO:0003684), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), enzyme binding (GO:0019899), mismatched DNA binding (GO:0030983), guanine/thymine mispair binding (GO:0032137), histone H3K36me3 reader activity (GO:0140003), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), magnesium ion binding (GO:0000287), four-way junction DNA binding (GO:0000400), DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), protein binding (GO:0005515), single guanine insertion binding (GO:0032142), single thymine insertion binding (GO:0032143), oxidized purine DNA binding (GO:0032357), MutLalpha complex binding (GO:0032405), ADP binding (GO:0043531)

GO Cellular Component (7): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), MutSalpha complex (GO:0032301), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Diseases of Mismatch Repair (MMR)	2
Mismatch Repair	1
DNA Repair	1
Diseases of DNA repair	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA metabolic process	2
DNA damage response	2
somatic diversification of immunoglobulins	2
binding	2
DNA binding	2
adenyl ribonucleotide binding	2
single base insertion or deletion binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
mismatch repair	1
meiosis I cell cycle process	1
DNA repair	1
developmental process involved in reproduction	1
male gamete generation	1
multicellular organismal process	1
intrinsic apoptotic signaling pathway	1
response to light stimulus	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immune receptors via germline recombination within a single locus	1
somatic recombination of immunoglobulin genes involved in immune response	1
B cell activation involved in immune response	1
regulation of DNA recombination	1
DNA recombination	1
negative regulation of DNA metabolic process	1
intracellular signal transduction	1
apoptotic signaling pathway	1
cellular component organization	1
cellular response to stress	1
negative regulation of macromolecule metabolic process	1
negative regulation of nucleobase-containing compound metabolic process	1
regulation of DNA metabolic process	1
purine ribonucleoside triphosphate binding	1
ATP hydrolysis activity	1
catalytic activity, acting on DNA	1
ATP-dependent activity	1
protein binding	1
double-stranded DNA binding	1
mismatched DNA binding	1
histone H3 reader activity	1

Protein interactions and networks

STRING

3570 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSH6	MLH1	P40692	999
MSH6	PMS2	P54278	999
MSH6	PMS1	P54277	998
MSH6	MLH3	P49751	995
MSH6	ATM	Q13315	994
MSH6	MSH2	P43246	992
MSH6	MSH3	P20585	992
MSH6	BRCA1	P38398	978
MSH6	MUTYH	Q9UIF7	976
MSH6	EXO1	Q9UQ84	973
MSH6	BRCA2	P51587	924
MSH6	RFC4	P35249	894
MSH6	BLM	P54132	884
MSH6	RFC2	P32846	879
MSH6	EPCAM	P16422	873

IntAct

125 interactions, top by confidence:

A	B	Type	Score
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
MSH6	MSH2	psi-mi:“MI:0915”(physical association)	0.910
MED9	MED19	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MCM9	MSH6	psi-mi:“MI:0915”(physical association)	0.620
KANK2	AIFM1	psi-mi:“MI:0914”(association)	0.600
MSH6	HRAS	psi-mi:“MI:0915”(physical association)	0.550
MSH6	PCNA	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
	MSH2	psi-mi:“MI:0914”(association)	0.500
	MSH2	psi-mi:“MI:0915”(physical association)	0.500
rep	NKRF	psi-mi:“MI:0914”(association)	0.500
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
PSMD4	MSH6	psi-mi:“MI:0915”(physical association)	0.400
MAP2K1	MSH6	psi-mi:“MI:0915”(physical association)	0.370
MSH6	NANS	psi-mi:“MI:0915”(physical association)	0.370
STK4	EIF3CL	psi-mi:“MI:0914”(association)	0.350
MSH6	PARP2	psi-mi:“MI:0914”(association)	0.350
Eif3i	CBX4	psi-mi:“MI:0914”(association)	0.350
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350
ANG	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (396): MSH6 (Affinity Capture-MS), MSH6 (Affinity Capture-MS), MSH6 (Affinity Capture-MS), MSH6 (Affinity Capture-RNA), ANKRD17 (Co-fractionation), FEN1 (Co-fractionation), HDGF (Co-fractionation), MSH6 (Co-fractionation), MSH6 (Co-fractionation), MSH6 (Co-fractionation), MSH6 (Co-fractionation), MSH6 (Co-fractionation), PCNA (Co-fractionation), RAD21 (Co-fractionation), MSH6 (Affinity Capture-MS)

ESM2 similar proteins: A1CDD4, A1CJ34, A1D8E4, A1DCB2, A2QY22, A2R1F6, A4R0R0, A4RN08, A5DEV6, A6R7S1, A6RPB6, A6ZTR3, A7EC69, B0YCF6, E1BYJ2, O04716, O74502, O74773, P0CO92, P0CO93, P13705, P20585, P25336, P38630, P52701, Q03834, Q0CPP9, Q0UCI9, Q0UXL8, Q1DQ73, Q1E5T3, Q2HFD4, Q2U6A1, Q2UE66, Q2UT70, Q4INS6, Q4P6I8, Q4WGB7, Q4WVG8, Q4WWE9

Diamond homologs: A0AIK5, A1CDD4, A1DCB2, A2R1F6, A2RJC8, A3DE67, A3LU10, A4R0R0, A4VSW4, A4VZ51, A4XL47, A5DEV6, A5DYV8, A5IMS8, A5N245, A6R7S1, A6RPB6, A6ZTR3, A7EC69, A7TTQ1, B0S1P2, B0YCF6, B1LC69, B3WC74, B4U143, B8D298, B8DFS4, B8I1Z8, B8I2Q5, B9E5U7, B9K937, B9KYW4, C0Z9F1, C1A4A9, C1L2V9, C6BSW8, O51125, O65607, P0CO92, P0CO93

SIGNOR signaling

2 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 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
Transcriptional regulation of granulopoiesis	7	9.9×	5e-03
Estrogen-dependent gene expression	8	6.8×	8e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

10375 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1792
Likely pathogenic	217
Uncertain significance	4421
Likely benign	1155
Benign	197

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027594	NC_000002.11:g.(48010633_48018065)_(48032167_48032756)del	Pathogenic
1048965	NM_000179.3(MSH6):c.3880del (p.Cys1294fs)	Pathogenic
1049101	NM_000179.3(MSH6):c.1089dup (p.Val364fs)	Pathogenic
1049210	NM_000179.3(MSH6):c.3647-2_3991del	Pathogenic
1049369	NM_000179.3(MSH6):c.1855G>T (p.Glu619Ter)	Pathogenic
1049393	NM_000179.3(MSH6):c.458-2_627+1del	Pathogenic
1049570	NM_000179.3(MSH6):c.3980_3981delinsTCAG (p.Asn1327fs)	Pathogenic
1049770	NM_000179.3(MSH6):c.1982del (p.Gly661fs)	Pathogenic
1050027	NM_000179.3(MSH6):c.3439-2_3556+1del	Pathogenic
1050249	NM_000179.3(MSH6):c.3860_3873dup (p.Gly1292fs)	Pathogenic
1050411	NM_000179.3(MSH6):c.2412_2413del (p.Lys804fs)	Pathogenic
1050732	NM_000179.3(MSH6):c.3083C>A (p.Ser1028Ter)	Pathogenic
1067408	NM_000179.3(MSH6):c.3646+1G>C	Pathogenic
1068512	NM_000179.3(MSH6):c.2335dup (p.Cys779fs)	Pathogenic
1068700	NM_000179.3(MSH6):c.2161A>T (p.Arg721Ter)	Pathogenic
1068844	NM_000179.3(MSH6):c.1671dup (p.Val558fs)	Pathogenic
1069248	NM_000179.3(MSH6):c.3424del (p.Thr1142fs)	Pathogenic
1069422	NM_000179.3(MSH6):c.92del (p.Gly31fs)	Pathogenic
1069424	NM_000179.3(MSH6):c.1421_1422del (p.Val474fs)	Pathogenic
1069438	NM_000179.3(MSH6):c.1586_1587insGATACAGTGTGCTGGAAGG (p.Asp530fs)	Pathogenic
1069466	NM_000179.3(MSH6):c.1661del (p.Arg554fs)	Pathogenic
1069523	NM_000179.3(MSH6):c.3709_3712dup (p.Thr1238fs)	Pathogenic
1069578	NM_000179.3(MSH6):c.2308_2311del (p.Gly770fs)	Pathogenic
1069617	NM_000179.3(MSH6):c.467C>A (p.Ser156Ter)	Pathogenic
1070674	NM_000179.3(MSH6):c.485del (p.Gly162fs)	Pathogenic
1070676	NM_000179.3(MSH6):c.717dup (p.Arg240fs)	Pathogenic
1070916	NM_000179.3(MSH6):c.3964_3980dup (p.Asn1327delinsLysAsnLeuArgArgTer)	Pathogenic
1070940	NM_000179.3(MSH6):c.3649_3655del (p.Arg1217fs)	Pathogenic
1071300	NM_000179.3(MSH6):c.979del (p.Thr327fs)	Pathogenic
1071468	NM_000179.3(MSH6):c.945dup (p.Arg316Ter)	Pathogenic

SpliceAI

1848 predictions. Top by Δscore:

Variant	Effect	Δscore
2:47790918:T:TA	acceptor_gain	1.0000
2:47790925:A:AG	acceptor_gain	1.0000
2:47790926:G:GG	acceptor_gain	1.0000
2:47790926:GTT:G	acceptor_gain	1.0000
2:47796049:G:GT	donor_gain	1.0000
2:47796061:G:GT	donor_gain	1.0000
2:47803682:ACAG:A	donor_loss	1.0000
2:47803683:CAGG:C	donor_loss	1.0000
2:47803684:AGGTA:A	donor_loss	1.0000
2:47803685:GG:G	donor_loss	1.0000
2:47803686:G:GC	donor_loss	1.0000
2:47803687:T:A	donor_loss	1.0000
2:47804905:CACA:C	acceptor_loss	1.0000
2:47804907:CA:C	acceptor_loss	1.0000
2:47804908:AG:A	acceptor_gain	1.0000
2:47804908:AGGCT:A	acceptor_gain	1.0000
2:47804909:GG:G	acceptor_gain	1.0000
2:47804909:GGCT:G	acceptor_gain	1.0000
2:47804909:GGCTG:G	acceptor_gain	1.0000
2:47805023:GTCAG:G	donor_gain	1.0000
2:47805024:TCAGG:T	donor_loss	1.0000
2:47805025:CAGGT:C	donor_loss	1.0000
2:47805026:AGG:A	donor_loss	1.0000
2:47805027:GGT:G	donor_loss	1.0000
2:47805028:G:T	donor_loss	1.0000
2:47805029:T:G	donor_loss	1.0000
2:47805614:TAAG:T	acceptor_loss	1.0000
2:47805615:A:AG	acceptor_gain	1.0000
2:47805615:AAG:A	acceptor_gain	1.0000
2:47805615:AAGGT:A	acceptor_gain	1.0000

AlphaMissense

8952 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:47799234:G:C	K417N	1.000
2:47799234:G:T	K417N	1.000
2:47799272:G:A	G430E	1.000
2:47799277:T:C	F432L	1.000
2:47799279:T:A	F432L	1.000
2:47799279:T:G	F432L	1.000
2:47799355:C:G	H458D	1.000
2:47799362:G:A	G460D	1.000
2:47803647:G:A	G1134R	1.000
2:47803647:G:C	G1134R	1.000
2:47803648:G:A	G1134E	1.000
2:47803655:T:A	N1136K	1.000
2:47803655:T:G	N1136K	1.000
2:47803658:G:A	M1137I	1.000
2:47803658:G:C	M1137I	1.000
2:47803658:G:T	M1137I	1.000
2:47803663:G:A	G1139D	1.000
2:47803668:T:C	S1141P	1.000
2:47803669:C:A	S1141Y	1.000
2:47803669:C:T	S1141F	1.000
2:47804998:G:C	R1176T	1.000
2:47805623:A:C	S1188R	1.000
2:47805625:T:A	S1188R	1.000
2:47805625:T:G	S1188R	1.000
2:47805698:G:C	D1213H	1.000
2:47805699:A:C	D1213A	1.000
2:47805699:A:T	D1213V	1.000
2:47805702:A:T	E1214V	1.000
2:47806204:G:A	G1216E	1.000
2:47806209:G:C	G1218R	1.000

dbSNP variants (sampled 300 via entrez): RS1000019294 (2:47795479 T>C), RS1000033277 (2:47797964 T>C,G), RS1000211091 (2:47782105 T>A,C), RS1000242323 (2:47782380 A>C), RS1000261186 (2:47793501 G>A,C), RS1000457359 (2:47796305 T>G), RS1000529606 (2:47794242 G>A), RS1000625241 (2:47794650 C>G,T), RS1000702910 (2:47806269 A>C,G,T), RS1000716886 (2:47790175 A>G), RS1000848897 (2:47794404 T>C), RS1000878445 (2:47784984 C>T), RS1000995838 (2:47794444 G>C), RS1001197893 (2:47783837 T>G), RS1001271348 (2:47784827 T>A)

Disease associations

OMIM: gene MIM:600678 | disease phenotypes: MIM:614350, MIM:619097, MIM:120435, MIM:276300, MIM:167000, MIM:114480, MIM:604370, MIM:613659, MIM:114500, MIM:176807, MIM:230800, MIM:608089, MIM:614337, MIM:618089

GenCC curated gene-disease

Disease	Classification	Inheritance
mismatch repair cancer syndrome 1	Definitive	Autosomal recessive
Lynch syndrome 5	Definitive	Autosomal dominant
mismatch repair cancer syndrome 3	Definitive	Autosomal recessive
Lynch syndrome	Definitive	Autosomal dominant
ovarian cancer	Strong	Autosomal dominant
rhabdomyosarcoma	Moderate	Autosomal recessive
Muir-Torre syndrome	Moderate	Autosomal dominant
malignant pancreatic neoplasm	Moderate	Autosomal dominant
breast cancer	Limited	Autosomal dominant
prostate cancer	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

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

Mondo (36): hereditary neoplastic syndrome (MONDO:0015356), Lynch syndrome (MONDO:0005835), colon carcinoma (MONDO:0002032), Lynch syndrome 5 (MONDO:0013710), endometrial carcinoma (MONDO:0002447), mismatch repair cancer syndrome 3 (MONDO:0030841), hereditary nonpolyposis colon cancer (MONDO:0018630), breast cancer (MONDO:0007254), Lynch syndrome 1 (MONDO:0007356), mismatch repair cancer syndrome 1 (MONDO:0010159), hereditary breast ovarian cancer syndrome (MONDO:0003582), ovarian cancer (MONDO:0008170), hereditary breast carcinoma (MONDO:0016419), rhabdomyosarcoma (MONDO:0005212), breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450)

Orphanet (14): Inherited cancer-predisposing syndrome (Orphanet:140162), Lynch syndrome (Orphanet:144), Hereditary nonpolyposis colon cancer (Orphanet:443909), Constitutional mismatch repair deficiency syndrome (Orphanet:252202), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Rare ovarian cancer (Orphanet:213500), Hereditary breast cancer (Orphanet:227535), Rhabdomyosarcoma (Orphanet:780), Serous carcinoma of the corpus uteri (Orphanet:213726), Hepatoblastoma (Orphanet:449), Familial prostate cancer (Orphanet:1331), Gaucher disease (Orphanet:355), Gaucher disease type 1 (Orphanet:77259), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

74 total (30 of 74 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: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:0001442	Typified by somatic mosaicism
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:0002354	Memory impairment
HP:0002376	Developmental regression
HP:0002516	Increased intracranial pressure

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001112_1	Lifetime average cigarettes per day in chronic obstructive pulmonary disease	2.000000e-07
GCST005312_6	Menopause (age at onset)	3.000000e-11
GCST006575_28	Takayasu arteritis	2.000000e-07
GCST006979_878	Heel bone mineral density	6.000000e-09
GCST007325_244	General risk tolerance (MTAG)	2.000000e-09
GCST008529_49	Tea consumption	8.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0010091	tea consumption measurement

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
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
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
D010049	Ovarian Diseases	C12.050.351.500.056.630; C12.100.250.056.630; C19.391.630
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.)
C563971	Colorectal Cancer, Hereditary Nonpolyposis, Type 4 (supp.)
C563456	Colorectal Cancer, Hereditary Nonpolyposis, Type 5 (supp.)
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)
C537243	Prostate cancer, familial (supp.)
C536928	Turcot syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4739849 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 5 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
MSH6 LOSS	Anti-PD-1 Monoclonal Antibody MEDI0680 + Durvalumab	Transitional Cell Carcinoma	Sensitivity/Response	CIViC C	EID1878

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3136228	MSH6		0.00	0

ChEMBL bioactivities

4 potent at pChembl≥5 of 6 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Kd	38	nM	MOLIBRESIB
7.31	Kd	49.46	nM	CHEMBL5653589
7.31	ED50	49.46	nM	CHEMBL5653589
7.22	IC50	60	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 12 total; 2 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179202: Binding affinity against MSH6 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0380	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148785: Binding affinity to human MSH6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0495	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, decreases expression, increases expression	4
sodium arsenite	affects cotreatment, decreases expression, decreases reaction	3
Resveratrol	decreases expression, affects cotreatment, increases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Tretinoin	decreases expression	3
Cadmium Chloride	decreases expression, decreases reaction	3
bisphenol A	affects expression, decreases expression	2
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	increases expression, affects response to substance	2
Cisplatin	decreases expression, affects response to substance	2
Copper	affects binding, decreases expression	2
Doxorubicin	decreases expression	2
Estradiol	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
lasiocarpine	increases metabolic processing, decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
titanium dioxide	decreases expression, affects binding	1
riddelliine	increases metabolic processing, decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
nivalenol	decreases expression	1
celastrol	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4736939	Binding	Binding affinity to MSH6 PWWP domain (unknown origin) assessed as aggregation temperature at 400 uM by heating at 25 to 85 degC by differential static light scattering method	Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. — J Med Chem

Cellosaurus cell lines

505 cell lines: 496 cancer cell line, 6 telomerase immortalized cell line, 1 hybrid cell line, 1 spontaneously immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0015	U-266/70	Cancer cell line	Male
CVCL_0016	U-266/84	Cancer cell line	Male
CVCL_0065	Jurkat	Cancer cell line	Male
CVCL_0076	SNU-16	Cancer cell line	Female
CVCL_0293	HEC-1-A	Cancer cell line	Female
CVCL_0294	HEC-1-B	Cancer cell line	Female
CVCL_0324	HuCC-T1	Cancer cell line	Male
CVCL_0354	J.CaM1.6	Cancer cell line	Male
CVCL_0367	Jurkat E6.1	Cancer cell line	Male
CVCL_0566	U266B1	Cancer cell line	Male

Clinical trials (associated diseases)

570 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