MSH3

mutS homolog 3, the group of MutS homologs

Basic information

Region (hg38): 5:80654652-80876815

Links

ENSG00000113318 ∙ NCBI:4437 ∙ OMIM:600887 ∙ HGNC:7326 ∙ Uniprot:P20585 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• familial adenomatous polyposis 4 (Moderate), mode of inheritance: AR
• MSH3-related attenuated familial adenomatous polyposis (Supportive), mode of inheritance: AR
• familial adenomatous polyposis 4 (Strong), mode of inheritance: AR
• familial adenomatous polyposis 4 (Strong), mode of inheritance: AR
• familial adenomatous polyposis 4 (Moderate), mode of inheritance: AR
• Lynch syndrome (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Endometrial carcinoma	AD	Oncologic	In HNPCC, for surveillance, colonoscopy with polyp removal is indicated starting at (whichever is earlier) age 20-25 years or 10 years prior to the earliest familial diagnosis; Prophylactic Hysterectomy with bilateral oophorectomy may be considered after childbearing is completed; For individuals with colon cancer, surgical treatment with full colectomy (and ileorectal anastomosis) is recommended; Cigarette smoking should be avoided; For other tumor types (individuals may be at risk for a number of cancer types), awareness of cancer risk may allow early diagnosis and treatment, which may reduce morbidity and mortality; Individuals with Mismatch repair cancer syndrome are at risk of multiple types of malignancy, and awareness may allow early detection and management	Oncologic	9354786; 12732731; 15098177; 15340263; 16000562; 16283678; 17557300; 24434690
Individuals may be at risk for a number of types of cancer

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MSH3 gene.

• not provided (172 variants)
• Familial adenomatous polyposis 4 (134 variants)
• Hereditary cancer-predisposing syndrome (95 variants)
• Endometrial carcinoma (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MSH3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			11	777	1	789
missense	1		2191	15	8	2215
nonsense	79	43	8			130
start loss			7			7
frameshift	207	61	3	7		278
inframe indel			51	15	2	68
splice donor/acceptor (+/-2bp)	2	76	14	2	1	95
splice region		5	108	129	7	249
non coding			20	419	73	512
Total	289	180	2305	1235	85

Highest pathogenic variant AF is 0.0000197

Variants in MSH3

This is a list of pathogenic ClinVar variants found in the MSH3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-80654678-C-G		not specified	Likely benign (Aug 15, 2023)
5-80654678-C-T			Benign (Jun 22, 2018)
5-80654686-C-T		not specified	Benign/Likely benign (Aug 15, 2023)
5-80654689-C-T			Benign (Jun 22, 2018)
5-80654693-A-G			Benign (Jun 22, 2018)
5-80654693-A-T		not specified	Likely benign (Jul 31, 2024)
5-80654693-A-AGGCCCTGCCGCCGGGCTGCCATCCT		Familial adenomatous polyposis 4	Benign (Nov 06, 2023)
5-80654697-C-CCTGCCGCCGGGCT		Familial adenomatous polyposis 4	Benign (Nov 06, 2023)
5-80654703-G-A		not specified	Likely benign (Aug 15, 2023)
5-80654704-CCGGGCTGCCATCCTTGCCCTGCCATGTCTCGCCGGAAGCCTGCGT-C			Uncertain significance (Aug 12, 2021)
5-80654720-G-T		not specified	Conflicting classifications of pathogenicity (Aug 15, 2023)
5-80654723-C-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Nov 23, 2022)
5-80654723-C-T		Hereditary cancer-predisposing syndrome • MSH3-related disorder	Uncertain significance (May 30, 2023)
5-80654724-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Mar 08, 2022)
5-80654725-G-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Feb 14, 2022)
5-80654725-GC-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 02, 2021)
5-80654726-C-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 21, 2022)
5-80654726-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Dec 05, 2022)
5-80654727-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Aug 23, 2023)
5-80654728-A-C			Uncertain significance (Jul 07, 2021)
5-80654728-A-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jun 17, 2024)
5-80654728-A-T		Hereditary cancer-predisposing syndrome • not specified	Uncertain significance (Sep 06, 2024)
5-80654729-T-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 16, 2023)
5-80654730-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Apr 24, 2023)
5-80654730-G-C			Uncertain significance (Mar 29, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MSH3	protein_coding	protein_coding	ENST00000265081	24	221813

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
7.44e-31	0.000312	125575	0	173	125748	0.000688

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.799	641	587	1.09	0.0000293	7434
Missense in Polyphen		202	199.94	1.0103		2447
Synonymous	0.0516	216	217	0.996	0.0000112	2163
Loss of Function	0.594	49	53.7	0.912	0.00000259	711

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00172	0.00170
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.00114	0.00114
Finnish	0.000693	0.000693
European (Non-Finnish)	0.000644	0.000624
Middle Eastern	0.00114	0.00114
South Asian	0.000851	0.000850
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: 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.
• Disease: DISEASE: 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. {ECO:0000305|PubMed:8782829}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:27476653}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Mismatch repair - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);Chromosomal and microsatellite instability in colorectal cancer;Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta);Mismatch Repair;DNA Repair (Consensus)

Recessive Scores

• pRec: 0.192

Intolerance Scores

• loftool: 0.117
• rvis_EVS: -0.08
• rvis_percentile_EVS: 47.26

Haploinsufficiency Scores

• pHI: 0.477
• hipred: Y
• hipred_score: 0.575
• ghis: 0.593

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.913

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Msh3
• Phenotype: digestive/alimentary phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); neoplasm; cellular phenotype; homeostasis/metabolism phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: meiotic mismatch repair;removal of nonhomologous ends;DNA repair;mismatch repair;mitotic recombination;reciprocal meiotic recombination;replication fork arrest;maintenance of DNA repeat elements;negative regulation of DNA recombination;positive regulation of helicase activity
• Cellular component: nucleus;nucleoplasm;membrane;mismatch repair complex;MutSbeta complex
• Molecular function: double-strand/single-strand DNA junction binding;damaged DNA binding;single-stranded DNA binding;protein binding;ATP binding;DNA-dependent ATPase activity;enzyme binding;mismatched DNA binding;guanine/thymine mispair binding;dinucleotide insertion or deletion binding;single guanine insertion binding;single thymine insertion binding;dinucleotide repeat insertion binding;oxidized purine DNA binding;protein homodimerization activity