MSH3
mutS homolog 3, the group of MutS homologs
Basic information
Region (hg38): 5:80654651-80876815
Links
Phenotypes
GenCC
Source:
- 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:
| 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
- not provided (3307 variants)
- Hereditary cancer-predisposing syndrome (2084 variants)
- Endometrial carcinoma (357 variants)
- Familial adenomatous polyposis 4 (281 variants)
- not specified (203 variants)
- MSH3-related condition (25 variants)
- Constitutional megaloblastic anemia with severe neurologic disease (9 variants)
- Inborn genetic diseases (7 variants)
- Endometrial carcinoma;Familial adenomatous polyposis 4 (3 variants)
- Diffuse midline glioma, H3 K27-altered (2 variants)
- Familial adenomatous polyposis 4;Endometrial carcinoma (2 variants)
- MSH3-related attenuated familial adenomatous polyposis (2 variants)
- Cavernous sinus meningioma (1 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 | 709 | 719 | ||||
| missense | 2011 | 14 | 2033 | |||
| nonsense | 78 | 40 | 126 | |||
| start loss | 7 | |||||
| frameshift | 186 | 60 | 256 | |||
| inframe indel | 47 | 14 | 63 | |||
| splice donor/acceptor (+/-2bp) | 71 | 12 | 88 | |||
| splice region ? | 3 | 106 | 108 | 7 | 224 | |
| non coding ? | 20 | 362 | 70 | 452 | ||
| Total | 267 | 171 | 2117 | 1108 | 81 |
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-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 | 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 (Oct 03, 2023) | ||
| 5-80654728-A-T | Hereditary cancer-predisposing syndrome • not specified | Uncertain significance (Jan 29, 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) | |||
| 5-80654731-T-A | Endometrial carcinoma | Uncertain significance (Sep 05, 2023) |
GnomAD
Source:
| 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:
- 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