MSH3

Summary

MSH3 (mutS homolog 3, HGNC:7326) is a protein-coding gene on chromosome 5q14.1, encoding DNA mismatch repair protein Msh3 (P20585). Component of the post-replicative DNA mismatch repair system (MMR).

The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer.

Source: NCBI Gene 4437 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial adenomatous polyposis 4 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 4,911 total — 378 pathogenic, 107 likely-pathogenic
• Phenotypes (HPO): 24
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_002439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7326
Approved symbol	MSH3
Name	mutS homolog 3
Location	5q14.1
Locus type	gene with protein product
Status	Approved
Aliases	DUP, MRP1
Ensembl gene	ENSG00000113318
Ensembl biotype	protein_coding
OMIM	600887
Entrez	4437

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000265081, ENST00000512258, ENST00000512531, ENST00000658259, ENST00000659302, ENST00000667069, ENST00000670357, ENST00000875834, ENST00000875835, ENST00000875836, ENST00000933917, ENST00000969133, ENST00000969134

RefSeq mRNA: 1 — MANE Select: NM_002439 NM_002439

CCDS: CCDS34195

Canonical transcript exons

ENST00000265081 — 24 exons

Exon	Start	End
ENSE00000757171	80792733	80792844
ENSE00000757174	80813584	80813741
ENSE00000757177	80854130	80854316
ENSE00000757181	80864813	80864942
ENSE00000757184	80873116	80873287
ENSE00001120405	80875751	80876815
ENSE00001163290	80778720	80778836
ENSE00001163296	80775694	80775758
ENSE00001163303	80768835	80769003
ENSE00001163310	80767933	80768120
ENSE00001163315	80761546	80761678
ENSE00001163339	80678927	80679093
ENSE00001191582	80672244	80672360
ENSE00001191589	80670097	80670309
ENSE00001191594	80665143	80665363
ENSE00001191598	80656411	80656531
ENSE00001244866	80654652	80654964
ENSE00001244880	80787565	80787672
ENSE00001505344	80674983	80675128
ENSE00001505345	80672741	80672858
ENSE00003479588	80725453	80725565
ENSE00003611519	80728851	80728965
ENSE00003633661	80744506	80744615
ENSE00003665469	80741464	80741548

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 95.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9089 / max 178.7572, expressed in 1812 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57316	10.9550	1777
57317	5.1178	1624
57318	1.4968	932
57319	1.3392	711

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.21	silver quality
bronchial epithelial cell	CL:0002328	94.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.17	gold quality
epithelium of bronchus	UBERON:0002031	93.21	gold quality
bronchus	UBERON:0002185	92.97	gold quality
secondary oocyte	CL:0000655	91.67	gold quality
oocyte	CL:0000023	87.81	gold quality
cardia of stomach	UBERON:0001162	87.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.47	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.39	gold quality
vena cava	UBERON:0004087	87.36	silver quality
renal medulla	UBERON:0000362	87.00	gold quality
lateral globus pallidus	UBERON:0002476	86.62	gold quality
subthalamic nucleus	UBERON:0001906	86.54	gold quality
calcaneal tendon	UBERON:0003701	86.54	gold quality
ventral tegmental area	UBERON:0002691	86.53	gold quality
corpus callosum	UBERON:0002336	86.37	gold quality
inferior vagus X ganglion	UBERON:0005363	86.23	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.14	gold quality
superior surface of tongue	UBERON:0007371	85.91	gold quality
pericardium	UBERON:0002407	85.82	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	85.74	gold quality
caput epididymis	UBERON:0004358	85.65	gold quality
pons	UBERON:0000988	85.59	gold quality
CA1 field of hippocampus	UBERON:0003881	85.45	gold quality
pylorus	UBERON:0001166	85.38	gold quality
substantia nigra pars compacta	UBERON:0001965	85.35	gold quality
nipple	UBERON:0002030	85.31	gold quality
superior vestibular nucleus	UBERON:0007227	85.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.22
E-CURD-112	no	2.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2, IRF6, NFKB

miRNA regulators (miRDB)

54 targeting MSH3, 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-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-627-3P	99.90	71.42	3316
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4727-5P	99.23	67.55	1154

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• Frequent LOH at hMLH1, a highly variable SNP in hMSH3, and negligible coding instability occur in ovarian cancer. (PMID:12014680)
• MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers. (PMID:14871813)
• This is the first report suggesting that genetic and epigenetic alterations in the human MSH3 gene might play a significant role in the progression of bladder tumors. (PMID:15541380)
• Plays a key role in the formation of CTG repeat expansions over successive generations in DM1 transgenic mice. (PMID:16552576)
• Polymorphisms in the mismatch repair gene, MSH3 is associated with colorectal cancer (PMID:17205513)
• Alterations in TGF-betaRII, BAX, IGFIIR, caspase-5, hMSH3 and hMSH6 genes of microsatellite instability are rare in urinary bladder carcinoma and they are not associated with microsatellite instability or the presence of p53 mutations. (PMID:17676485)
• Mutations at the mononucleotide repeats within the hMSH3 gene occurred in certain basal cell carcinomas, not always in association with microsatellite instability . (PMID:17950544)
• Mismatch repair gene MSH3 polymorphism is associated with the risk of sporadic prostate cancer (PMID:18355840)
• Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. (PMID:18922920)
• The human DNA mismatch complex MSH2-MSH3 recognizes small loops by a mechanism different from that of MSH2-MSH6 for single-base mismatches. (PMID:19377479)
• MutSbeta displays identical biochemical and biophysical activities when interacting with a (CAG)(n) hairpin and a mismatch.[MutSbeta] (PMID:19525234)
• methylation of hMLH1 and hMSH3 is age related and thus may play an important role in gastric carcinogenesis in the elderly. (PMID:19894224)
• the MutSbeta-MutLalpha interaction is mediated in part by residues ((L/I)SRFF) embedded within the MSH3 PCNA-binding motif (PMID:20154325)
• Strong role of MutSbeta in insertion-deletions repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability. (PMID:20160730)
• Endoscopic biopsy provides equal accuracy and easier interpretation of MMRP expression immunostaining compared to surgical resection specimens. (PMID:20632816)
• Loss of hMSH3 corresponds with multiple tetranucleotide frameshifts. The association between EMAST and ulcerated tumors might result from increased inflammation. (PMID:20708618)
• Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. (PMID:20845481)
• No association of tumor necrosis with expression of p53, bcl-2, and mismatch repair protein status was observed in colorectal cancers. (PMID:20869096)
• We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes. (PMID:21128252)
• Results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. (PMID:21285347)
• Stress treatment of mouse cells with ethanol or hydrogen peroxide caused the re-distribution of MSH3 into nuclear bodies containing the proliferating cell nuclear antigen (PCNA), a known binding partner of MutSbeta. (PMID:21344488)
• Complex MSH2/MSH3 discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of the junctions. MSH2/MSH3 binds, bends and dissociates from repair-competent loops to signal downstream repair. (PMID:21960445)
• polymorphisms in MSH3 do not contribute to cancer risk in a population of Lynch syndrome patients with colorectal cancer (PMID:21974800)
• two novel HLA-A0201-restricted cytotoxic T cell epitopes derived from a (-1) frameshift mutation of a coding A(8) tract within the MSH3 gene (PMID:22110587)
• Studies indicate thar eukaryotes MutSbeta, a heterodimer of Msh2 and Msh3, recognizes insertion-deletion loops (IDLs) of 1-15 nucleotides, as well as DNA with a 3’ single-stranded overhang. (PMID:22179786)
• The high frequency of loss of heterozygosity as well as the aberrant protein expression in some tumors indicates an involvement of MSH3 impairment in colorectal cancer with low-level microsatellite instability. (PMID:22249440)
• The binding of HIF-1alpha complexes to hypoxia response element sites is necessary for down-regulation of hMSH3 in both wt-p53 and mut-p53 cells. (PMID:22343000)
• siRNA knockdown of the MutSbeta subunits MSH2 or MSH3 impeded expansion of threshold-length CTG*CAG repeats. (PMID:22941650)
• Oxidative stress, which causes a shift of hMSH3’s subcellular location, may contribute to an hMSH3 loss-of-function phenotype by sequestering it to the cytosol (PMID:23226332)
• Single nucleotide polymorphisms in MSH3 are associated with myelodysplastic syndromes. (PMID:23339595)
• MSH3 status can regulate the DNA damage response and extent of apoptosis induced by chemotherapy. (PMID:23724141)
• Methylation of MSH3 together with exposure to tobacco smoke is involved in esophageal carcinogenesis. (PMID:24934723)
• IL6 signaling disrupts the nuclear localization of hMSH3 and DNA repair, leading to elevated microsatellite alterations at selected tetranucleotide repeats in cancer cell lines. (PMID:25461668)
• Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of head and neck squamous cell carcinoma (PMID:25598504)
• Data show that single nucleotide polymorphisms in MutS homolog 3 (MSH3) had an impact on the chemotherapy response and prognosis of advanced non-small cell lung cancer (NCSLC) patients who were treated with platinum-based chemotherapy. (PMID:25966119)
• The mismatch-binding protein MutS beta, a heterodimer of MSH2 and MSH3, activates ATR in response to DNA double-strand breaks. (PMID:26212458)
• Our meta-analysis results demonstrated that MSH3 rs26279 G > A polymorphism is associated with an increased risk of overall cancer, especially for the colorectal cancer and breast cancer. (PMID:26617824)
• Three polymorphisms in MSH3 were associated with variation in somatic instability in myotonic dystrophy type 1. (PMID:26994442)
• data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis (PMID:27476653)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	msh3	ENSDARG00000063276
mus_musculus	Msh3	ENSMUSG00000014850
rattus_norvegicus	Msh3	ENSRNOG00000064838

Paralogs (4): MSH4 (ENSG00000057468), MSH2 (ENSG00000095002), MSH6 (ENSG00000116062), MSH5 (ENSG00000204410)

Protein

Protein identifiers

DNA mismatch repair protein Msh3 — P20585 (reviewed: P20585)

Alternative names: Divergent upstream protein, Mismatch repair protein 1

All UniProt accessions (5): A0A590UJN8, A0A590UJW0, A0A590UK39, A0A590UKC9, P20585

UniProt curated annotations — full annotation on UniProt →

Function. Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS beta which binds to DNA mismatches thereby initiating DNA repair. When bound, the MutS beta heterodimer bends the DNA helix and shields approximately 20 base pairs. MutS beta recognizes large insertion-deletion loops (IDL) up to 13 nucleotides long. 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.

Subunit / interactions. Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1. Heterodimer consisting of MSH2-MSH3 (MutS beta). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with EXO1. Interacts with MCM9.

Disease relevance. 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. Familial adenomatous polyposis 4 (FAP4) [MIM:617100] A form of familial adenomatous polyposis, a condition characterized by the development of multiple colorectal adenomatous polyps, benign neoplasms derived from glandular epithelium. Some affected individuals may develop colorectal carcinoma. FAP4 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutS family. MSH3 subfamily.

RefSeq proteins (1): NP_002430* (*=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
IPR016151	DNA_mismatch_repair_MutS_N	Homologous_superfamily
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, PF01624, PF05188, PF05192

UniProt features (114 total): helix 42, strand 38, turn 12, sequence variant 8, compositionally biased region 5, region of interest 3, modified residue 2, sequence conflict 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

24 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
8R7E	X-RAY DIFFRACTION	2.78
8R7C	X-RAY DIFFRACTION	2.82
8RAZ	X-RAY DIFFRACTION	2.84
3THY	X-RAY DIFFRACTION	2.89
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
8OMA	ELECTRON MICROSCOPY	3.29
8OM9	ELECTRON MICROSCOPY	3.32
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-P20585-F1	79.48	0.61

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): 896–903

Post-translational modifications (2): 33, 1099

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
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-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: 253 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, MORF_MSH3, MORF_BRCA1, MORF_ATRX, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MORF_ESR1, KAUFFMANN_DNA_REPAIR_GENES, MORF_RAD51L3, MUELLER_PLURINET, MORF_PPP5C, KEGG_PATHWAYS_IN_CANCER

GO Biological Process (7): DNA repair (GO:0006281), mismatch repair (GO:0006298), mitotic recombination (GO:0006312), somatic recombination of immunoglobulin gene segments (GO:0016447), maintenance of DNA repeat elements (GO:0043570), negative regulation of DNA recombination (GO:0045910), DNA damage response (GO:0006974)

GO Molecular Function (12): double-stranded DNA binding (GO:0003690), ATP binding (GO:0005524), enzyme binding (GO:0019899), mismatched DNA binding (GO:0030983), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), DNA binding (GO:0003677), single-stranded DNA binding (GO:0003697), protein binding (GO:0005515), dinucleotide insertion or deletion binding (GO:0032139), single guanine insertion binding (GO:0032142), dinucleotide repeat insertion binding (GO:0032181)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), MutSbeta complex (GO:0032302)

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
DNA metabolic process	2
DNA recombination	2
DNA binding	2
cellular anatomical structure	2
DNA damage response	1
DNA repair	1
somatic diversification of immune receptors via germline recombination within a single locus	1
somatic diversification of immunoglobulins	1
chromosome organization	1
regulation of DNA recombination	1
negative regulation of DNA metabolic process	1
cellular response to stress	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein binding	1
double-stranded DNA binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid binding	1
binding	1
DNA insertion or deletion binding	1
single base insertion or deletion binding	1
dinucleotide insertion or deletion binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
mismatch repair complex	1
nuclear protein-containing complex	1

Protein interactions and networks

STRING

1998 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSH3	MLH1	P40692	999
MSH3	PMS2	P54278	998
MSH3	MLH3	P49751	996
MSH3	PMS1	P54277	995
MSH3	MSH2	P43246	992
MSH3	MSH6	P52701	992
MSH3	EXO1	Q9UQ84	957
MSH3	SLX4	Q8IY92	955
MSH3	OGG1	P78554	910
MSH3	SLX1A	Q9BQ83	830
MSH3	MUS81	Q96NY9	812
MSH3	MUTYH	Q9UIF7	810
MSH3	ERCC1	P07992	800
MSH3	FEN1	P39748	790
MSH3	POLE	Q07864	776

IntAct

100 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
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
MLH1	MSH3	psi-mi:“MI:0915”(physical association)	0.740
MSH3	MLH1	psi-mi:“MI:0915”(physical association)	0.740
PCNA	MSH3	psi-mi:“MI:0915”(physical association)	0.720
MSH3	PCNA	psi-mi:“MI:0915”(physical association)	0.720
H2AC4	PPM1G	psi-mi:“MI:0914”(association)	0.670
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
SLC39A9	B4GALT5	psi-mi:“MI:0914”(association)	0.530
KBTBD7	PLD2	psi-mi:“MI:0914”(association)	0.530
MCM9	MSH3	psi-mi:“MI:0914”(association)	0.460

BioGRID (178): MSH3 (Two-hybrid), PCNA (Two-hybrid), MSH3 (Co-fractionation), MSH3 (Co-fractionation), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Affinity Capture-MS), MSH3 (Two-hybrid), MSH3 (Affinity Capture-MS)

ESM2 similar proteins: A1CDD4, A1CJ34, A1D8E4, A1DCB2, A2QY22, A2R1F6, A4R0R0, A6R7S1, A6RPB6, A7EC69, B0YCF6, G0S8F1, O24617, O74502, O74773, P0CO92, P0CO93, P0CQ16, P0CQ17, P13705, P20585, P30664, P54898, Q01317, Q03834, Q0CPP9, Q0UXL8, Q1DKE7, Q1DQ73, Q2HFD4, Q2U6A1, Q2UT70, Q4INS6, Q4IQC1, Q4P6I8, Q4PEJ3, Q4WGB7, Q4WVG8, Q4WWE9, Q4WYE5

Diamond homologs: A0LG76, A0Q0M6, A1CDD4, A1DCB2, A2R1F6, A2RGX2, A2RP10, A3CR17, A3LU10, A4R0R0, A4W4J7, A5DEV6, A5DYV8, A6R7S1, A6RPB6, A6ZTR3, A7EC69, A7TTQ1, A8AZU4, B0YCF6, B1I9E5, B3E6P2, B4UCY7, B5E385, B5XJ75, B8CX98, B8I2Q5, B8JA66, B8ZPK0, B9DW73, B9MJU0, C0MAS5, C0MGC5, C0ZEZ4, C1CAQ5, C1CH06, C1CN23, C1CTY2, C4L191, O65607

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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
Dual incision in TC-NER	5	17.7×	1e-03
DNA Repair	7	14.1×	1e-04
RUNX1 regulates transcription of genes involved in differentiation of HSCs	5	9.7×	6e-03
Estrogen-dependent gene expression	6	9.3×	3e-03
Dengue Virus-Host Interactions	8	7.5×	1e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

4911 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	378
Likely pathogenic	107
Uncertain significance	2589
Likely benign	1410
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068515	NM_002439.5(MSH3):c.2413del (p.Ala805fs)	Pathogenic
1069524	NM_002439.5(MSH3):c.2564_2565del (p.Arg855fs)	Pathogenic
1069648	NM_002439.5(MSH3):c.2207_2208del (p.Ile736fs)	Pathogenic
1069698	NM_002439.5(MSH3):c.2420G>A (p.Trp807Ter)	Pathogenic
1070247	NM_002439.5(MSH3):c.667A>T (p.Lys223Ter)	Pathogenic
1070753	NM_002439.5(MSH3):c.1412_1420delinsGGTAATATACATCACATTCAAGATAATGTTTGCTTCTTTTATTAATTTTTTTTTTTAATTTGAGACGATGTTTCACTCTTGCTCAGGCTGGAGTGCAGTGGTGTGATCACAGCTCATTGCAGCCTTGACTCCCTGGGCTCAAGTGATCCTCCCACCTCAGCCTTCCAAGTAGCTGGGACTACAGGCATGTGCTACCGTGCCTGGCTAATTTTTGTATTTTTTGTAGAGAGAGCCATGTTGCCCAGGCTGGTCTTAAACTCCTGAGCTCAGGCAGTCCTCCTGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCATTAAGCCACCGTGCCCGGCCAGCGTTTCCTTCTGGAAATCGTAGAGGGATGTGATT (p.Ala471_Glu474delinsGlyTer)	Pathogenic
1072068	NM_002439.5(MSH3):c.721C>T (p.Gln241Ter)	Pathogenic
1072147	NM_002439.5(MSH3):c.747T>A (p.Cys249Ter)	Pathogenic
1072399	NC_000005.9:g.(?80088542)(80088673_?)del	Pathogenic
1072789	NM_002439.5(MSH3):c.2042del (p.Pro681fs)	Pathogenic
1073059	NM_002439.5(MSH3):c.1907_1908del (p.Gln636fs)	Pathogenic
1073685	NM_002439.5(MSH3):c.2530_2534del (p.Gly844fs)	Pathogenic
1073699	NM_002439.5(MSH3):c.1434del (p.Asp479fs)	Pathogenic
1073766	NM_002439.5(MSH3):c.1575dup (p.Lys526Ter)	Pathogenic
1073913	NM_002439.5(MSH3):c.1597G>T (p.Glu533Ter)	Pathogenic
1074045	NM_002439.5(MSH3):c.594del (p.Phe198fs)	Pathogenic
1074255	NC_000005.9:g.(?80109393)(80109570_?)del	Pathogenic
1074256	NC_000005.9:g.(?80149939)(80150145_?)del	Pathogenic
1074258	NC_000005.9:g.(?79965906)(79974922_?)del	Pathogenic
1074334	NM_002439.5(MSH3):c.574dup (p.Gln192fs)	Pathogenic
1074482	NM_002439.5(MSH3):c.827del (p.His275_Leu276insTer)	Pathogenic
1074951	NM_002439.5(MSH3):c.2100_2101del (p.Glu701fs)	Pathogenic
1074977	NM_002439.5(MSH3):c.2392C>T (p.Gln798Ter)	Pathogenic
1075462	NM_002439.5(MSH3):c.1744C>T (p.Gln582Ter)	Pathogenic
1076536	NM_002439.5(MSH3):c.2739del (p.Ile914fs)	Pathogenic
1076787	NM_002439.5(MSH3):c.1992del (p.Gln664fs)	Pathogenic
1356132	NM_002439.5(MSH3):c.1499_1500insGG (p.Ile500fs)	Pathogenic
1358379	NM_002439.5(MSH3):c.762T>A (p.Tyr254Ter)	Pathogenic
1358390	NM_002439.5(MSH3):c.3220A>T (p.Lys1074Ter)	Pathogenic
1358755	NM_002439.5(MSH3):c.503dup (p.Asp168fs)	Pathogenic

SpliceAI

5254 predictions. Top by Δscore:

Variant	Effect	Δscore
5:80654961:CATA:C	donor_gain	1.0000
5:80654962:ATA:A	donor_gain	1.0000
5:80654963:TA:T	donor_gain	1.0000
5:80654963:TAGTA:T	donor_loss	1.0000
5:80654964:AG:A	donor_loss	1.0000
5:80654965:G:GG	donor_gain	1.0000
5:80654965:GTAG:G	donor_loss	1.0000
5:80654966:T:A	donor_loss	1.0000
5:80656407:ATAG:A	acceptor_gain	1.0000
5:80656408:TA:T	acceptor_loss	1.0000
5:80656495:G:GT	donor_gain	1.0000
5:80656502:G:GT	donor_gain	1.0000
5:80656528:TCTGG:T	donor_loss	1.0000
5:80656529:CTGG:C	donor_loss	1.0000
5:80656530:TGGT:T	donor_loss	1.0000
5:80656531:GGTG:G	donor_loss	1.0000
5:80656532:G:GG	donor_gain	1.0000
5:80656532:G:T	donor_loss	1.0000
5:80656533:T:G	donor_loss	1.0000
5:80665129:A:AG	acceptor_gain	1.0000
5:80665129:ATTT:A	acceptor_gain	1.0000
5:80665130:T:G	acceptor_gain	1.0000
5:80665132:T:TA	acceptor_gain	1.0000
5:80665135:T:A	acceptor_gain	1.0000
5:80665140:A:AG	acceptor_gain	1.0000
5:80665141:A:AG	acceptor_gain	1.0000
5:80665142:G:GG	acceptor_gain	1.0000
5:80665360:AAAGG:A	donor_loss	1.0000
5:80665362:AGG:A	donor_loss	1.0000
5:80665364:GTAT:G	donor_loss	1.0000

AlphaMissense

7482 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:80672305:T:A	I285K	0.999
5:80672341:T:C	L297P	0.999
5:80792822:T:A	V878D	0.999
5:80854183:T:C	L956P	0.999
5:80864906:T:C	F1032L	0.999
5:80864908:C:A	F1032L	0.999
5:80864908:C:G	F1032L	0.999
5:80873203:C:A	A1073D	0.999
5:80670275:G:A	G253E	0.998
5:80672260:T:C	L270P	0.998
5:80672298:G:C	A283P	0.998
5:80672299:C:A	A283E	0.998
5:80672305:T:G	I285R	0.998
5:80672317:G:C	R289T	0.998
5:80672338:G:C	R296P	0.998
5:80778737:G:C	R779P	0.998
5:80813615:G:A	G896E	0.998
5:80813622:C:A	N898K	0.998
5:80813622:C:G	N898K	0.998
5:80813625:G:A	M899I	0.998
5:80813625:G:C	M899I	0.998
5:80813625:G:T	M899I	0.998
5:80813630:G:A	G901E	0.998
5:80813632:A:C	K902Q	0.998
5:80813635:A:C	S903R	0.998
5:80813637:C:A	S903R	0.998
5:80813637:C:G	S903R	0.998
5:80873148:T:C	F1055L	0.998
5:80873150:C:A	F1055L	0.998
5:80873150:C:G	F1055L	0.998

dbSNP variants (sampled 300 via entrez): RS1000011853 (5:80865692 A>C), RS1000013862 (5:80843080 C>A), RS1000017725 (5:80789034 T>A), RS1000028682 (5:80782692 A>C,T), RS1000045531 (5:80872253 T>G), RS1000045850 (5:80825079 G>A), RS1000066292 (5:80843339 C>T), RS1000068815 (5:80709958 T>A,C), RS1000114825 (5:80674030 C>T), RS1000122054 (5:80837394 T>C), RS1000125746 (5:80669204 C>T), RS1000129561 (5:80693823 A>C), RS1000159994 (5:80837201 A>C,G,T), RS1000171431 (5:80826307 C>T), RS1000214600 (5:80756357 G>A,T)

Disease associations

OMIM: gene MIM:600887 | disease phenotypes: MIM:617100

GenCC curated gene-disease

Disease	Classification	Inheritance
familial adenomatous polyposis 4	Definitive	Autosomal recessive
MSH3-related attenuated familial adenomatous polyposis	Supportive	Autosomal recessive
Lynch syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
familial adenomatous polyposis 4	Definitive	AR
Lynch syndrome	Disputed	AD

Mondo (6): hereditary neoplastic syndrome (MONDO:0015356), endometrial carcinoma (MONDO:0002447), familial adenomatous polyposis 4 (MONDO:0044300), diffuse midline glioma, H3 K27-altered (MONDO:1060171), Lynch syndrome (MONDO:0005835), (MONDO:0018812)

Orphanet (2): Inherited cancer-predisposing syndrome (Orphanet:140162), MSH3-related polyposis (Orphanet:480536)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000107	Renal cyst
HP:0000131	Uterine leiomyoma
HP:0000138	Ovarian cyst
HP:0000854	Thyroid adenoma
HP:0001442	Typified by somatic mosaicism
HP:0003003	Colon cancer
HP:0003596	Middle age onset
HP:0004394	Multiple gastric polyps
HP:0004783	Duodenal polyposis
HP:0004784	Juvenile gastrointestinal polyposis
HP:0005227	Adenomatous colonic polyposis
HP:0008069	Neoplasm of the skin
HP:0009592	Astrocytoma
HP:0011462	Young adult onset
HP:0012114	Endometrial carcinoma
HP:0012126	Stomach cancer
HP:0012740	Papilloma
HP:0025274	Ovarian dermoid cyst
HP:0033770	Gastric adenocarcinoma
HP:0100743	Neoplasm of the rectum
HP:0200063	Colorectal polyposis
HP:6000102	Breast intraductal papilloma

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004691_1	Huntington’s disease progression	1.000000e-10
GCST004691_11	Huntington’s disease progression	4.000000e-06
GCST004763_5	HDL cholesterol change in response to fenofibrate in statin-treated type 2 diabetes	1.000000e-08
GCST010172_4	Idiopathic downbeat nystagmus	4.000000e-06
GCST010701_1	Cortical surface area (MOSTest)	1.000000e-08
GCST010702_52	Subcortical volume (MOSTest)	8.000000e-10
GCST010703_285	Brain morphology (MOSTest)	4.000000e-15

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression measurement
EFO:0007805	HDL cholesterol change measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

10 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs408626	DHFR, MSH3	3	5.50	1	methotrexate
rs442767	DHFR, MSH3	3	2.25	2	pemetrexed;methotrexate
rs1105525	DHFR, MSH3	3	2.75	1	methotrexate
rs1650697	DHFR, MSH3	3	2.50	1	pemetrexed
rs10072026	DHFR, MSH3		0.00	0
rs70991108	DHFR, MSH3	3	0.50	1	methotrexate
rs3045983	DHFR, MSH3		0.00	0
rs863221	MSH3		0.00	0
rs26279	MSH3		0.00	0
rs200850015	DHFR, MSH3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	3
Doxorubicin	affects response to substance, decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
pradimicin-IRD	increases expression, affects expression, affects response to substance	1
myristicin	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
quinoline yellow	increases expression	1
potassium chromate(VI)	decreases expression	1
isobutyl alcohol	increases abundance, affects cotreatment, decreases expression	1
cylindrospermopsin	increases expression	1
chloropicrin	increases expression	1
vandetanib	decreases expression	1
ICG 001	increases expression	1
fenbuconazole	decreases expression	1
olaparib	decreases response to substance	1
bisphenol S	affects cotreatment, decreases expression	1
Oxaliplatin	increases expression, increases reaction, affects localization, increases phosphorylation, decreases response to substance	1
Resveratrol	affects cotreatment, increases expression	1
Zoledronic Acid	increases expression	1
Carcinogens	decreases expression	1
Cisplatin	decreases response to substance	1
Coumestrol	decreases expression	1
Cycloheximide	decreases expression, decreases reaction	1
Dexamethasone	affects cotreatment, decreases expression	1
Gasoline	increases abundance, affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Mutagens	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8KU	Abcam HCT 116 MSH3 KO	Cancer cell line	Male
CVCL_B9N1	Abcam A-549 MSH3 KO	Cancer cell line	Male
CVCL_D2GG	Abcam MCF-7 MSH3 KO	Cancer cell line	Female
CVCL_SY96	HAP1 MSH3 (-) 1	Cancer cell line	Male
CVCL_SY97	HAP1 MSH3 (-) 2	Cancer cell line	Male
CVCL_SY98	HAP1 MSH3 (-) 3	Cancer cell line	Male
CVCL_VP18	SVG-A Msh3-/-	Transformed cell line	Male
CVCL_VP19	SVG-A Msh3 1.7X	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00719017	PHASE4	UNKNOWN	Upper Vaginectomy Versus Brachytherapy in Patients With Early Stage Endometrial Cancer Treated With Laparoscopic Surgery
NCT02543710	PHASE4	RECRUITING	Biomarker Guided Treatment in Gynaecological Cancer
NCT03349463	PHASE4	UNKNOWN	Evaluation of Fluciclovine Uptake in Patients With Cervical, Ovarian Epithelial or Endometrial Cancers.
NCT03752606	PHASE4	COMPLETED	Application of Tachosil During Lymphadenectomy
NCT05949424	PHASE4	UNKNOWN	OPTI - DOSE: Optimal Dosing of Oral Anticancer Drugs in Older Adults
NCT06049693	PHASE4	COMPLETED	Iron Prehabilitation in Endometrial Cancer
NCT06726291	PHASE4	RECRUITING	Akynzeo as Antiemetic Treatment in Patients With Endometrial Cancer
NCT06871787	PHASE4	NOT_YET_RECRUITING	Near-Infrared Fluorescence Imaging With Indocyanine Green to Evaluate Bowel Anastomoses in Gynecologic Oncology Surgery
NCT07281547	PHASE4	NOT_YET_RECRUITING	Low Dose Aspirin to Lower Inflammation and Prevent Endometrial Cancer in Postmenopausal Women With Non-atrophic Endometrial Changes and Pain
NCT07462663	PHASE4	NOT_YET_RECRUITING	SHAPE-ENDO: Multimodal Pre-Surgical Optimization in Patients With Obesity and Early-Stage Endometrial Cancer (Phase 1)
NCT00566644	PHASE3	TERMINATED	Intrauterine Levonorgestrel and Observation or Observation Alone in Preventing Atypical Endometrial Hyperplasia and Endometrial Cancer in Women With Hereditary Non-Polyposis Colorectal Cancer or Lynch Syndrome
NCT02000089	PHASE3	RECRUITING	The Cancer of the Pancreas Screening-5 CAPS5)Study
NCT02813824	PHASE3	ACTIVE_NOT_RECRUITING	Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome
NCT02912559	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
NCT04711434	PHASE3	UNKNOWN	PD-1 Antibody for The Prevention of Adenomatous Polyps and Second Primary Tumors in Lynch Syndrome Patients
NCT07609901	PHASE3	NOT_YET_RECRUITING	Preventive Dendritic Cell Vaccination for Lynch Syndrome Carriers
NCT00002459	PHASE3	COMPLETED	Radiation Therapy or No Further Treatment Following Surgery in Treating Patients With Cancer of the Uterus
NCT00002493	PHASE3	COMPLETED	Radiation Therapy Compared With Combination Chemotherapy in Treating Patients With Advanced Endometrial Cancer
NCT00002641	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Soft Tissue Sarcoma
NCT00002764	PHASE3	COMPLETED	Surgery With or Without Combination Chemotherapy in Treating Patients With Lung Metastases From Soft Tissue Sarcoma
NCT00002920	PHASE3	COMPLETED	S9630, Medroxyprogesterone in Treating Women With Breast Cancer
NCT00002976	PHASE3	TERMINATED	Estrogen Replacement Therapy in Treating Women With Early-Stage Endometrial Cancer
NCT00003267	PHASE3	COMPLETED	Pelvic Drains After Radical Hysterectomy in Treating Patients With Uterine, Cervical, or Vaginal Cancer
NCT00003691	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Patients With Stage III, Stage IV, or Recurrent Endometrial Cancer
NCT00003749	PHASE3	COMPLETED	Surgery With or Without Lymphadenectomy and Radiation Therapy in Treating Patients With Endometrial Cancer
NCT00005583	PHASE3	COMPLETED	Radiation Therapy With or Without Chemotherapy in Treating Patients With High-Risk Endometrial Cancer
NCT00006027	PHASE3	COMPLETED	Comparison of Radiation Therapy With or Without Combination Chemotherapy Following Surgery in Treating Patients With Stage I or Stage II Endometrial Cancer
NCT00016341	PHASE3	TERMINATED	Combination Chemotherapy Compared With Hormone Therapy in Treating Patients With Recurrent, Stage III, or Stage IV Endometrial Cancer
NCT00033605	PHASE3	COMPLETED	Octreotide in Preventing Diarrhea in Patients Who Are Undergoing Radiation Therapy to the Pelvis
NCT00096408	PHASE3	COMPLETED	Laparoscopic Approach to Cancer of the Endometrium
NCT00245050	PHASE3	COMPLETED	Pyridoxine in Preventing Hand-Foot Syndrome in Patients Who Are Receiving Liposomal Doxorubicin for Cancer
NCT00376844	PHASE3	COMPLETED	External-Beam Radiation Therapy Compared With Vaginal Brachytherapy After Surgery for Stage I Endometrial Cancer
NCT00411138	PHASE3	UNKNOWN	Randomized Trial of Radiation Therapy With or Without Chemotherapy for Endometrial Cancer
NCT00883116	PHASE3	TERMINATED	A Study of Ixabepilone as Second-line Therapy for Locally Advanced, Recurrent, or Metastatic Endometrial Cancer
NCT01087268	PHASE3	UNKNOWN	Hyperbaric Oxygen Therapy in Treating Long-Term Gastrointestinal Adverse Effects Caused by Radiation Therapy in Patients With Pelvic Cancer
NCT01470677	PHASE3	COMPLETED	Tachosil for the Prevention of Symptomatic Lymph Cysts
NCT01672892	PHASE3	COMPLETED	Standard Versus Intensity-Modulated Pelvic Radiation Therapy in Treating Patients With Endometrial or Cervical Cancer
NCT01767155	PHASE3	COMPLETED	Zoptarelin Doxorubicin (AEZS 108) as Second Line Therapy for Endometrial Cancer
NCT02584478	PHASE3	UNKNOWN	Phase 1/2a/3 Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002)