MSH2
protein-codingmutS homolog 2, the group of MutS homologs
Gene summary
This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
- COCA1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~260.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008170
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0009831
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: ClinGen
Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [MONDO:0018630], is a group of autosomal dominant cancer predisposing syndrome. 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. MSH2 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8261515 and 8252616). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately. MSH2 gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. Loss of function variants in MSH2 gene have been repetitively reported in families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eight loss of function variants in this gene reported in 9 probands from 9 families in 2 publications (PMID:18566915, 32161499) is included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by expression, functional studies (6 points) demonstrating MSH2’s role in mismatch repair and mouse models (PMIDs: 19324997, 7550317, 7628020). Homozygous Msh2-/- mice began, with high frequency, to develop lymphoid tumors containing microsatellite instabilities at an early age. In addition, Msh2-deficient mouse ES cells lost mismatch binding and acquired microsatellite instability. In summary, MSH2 is definitively associated with autosomal dominant Lynch syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0007254
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008018
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008315
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: ClinGen
There has been sufficient amount of evidence published associating the MSH2 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from the dominant Lynch syndrome - since the gene-disease relationship was first proposed by Whiteside D, et al., (2002). Multiple case level studies have been performed with cMMRD syndrome patients that have variants in the MSH2 gene. Other mismatch repair (MMR) genes MLH1, MSH6 and PMS2 also causes constitutional mismatch repair deficiency syndrome. RNA and Immunoblotting demonstrate a lack of MSH2 protein in patient cells. Multiple MSH2 deficient mouse and zebrafish models have been established to show consistent phenotypes with cMMRD patients by developing neurofibromas and lymphoid tumors. There is sufficient evidence consistent with a definitive relationship between the MSH2 gene and constitutional mismatch repair deficiency syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0007356
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0030840
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007356
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007356
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: ClinGen
*MSH2* gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. MSH2 has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. This curation focuses on refuting the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data and experimental data. **Summary of Case-Control Data: 0 POINTS** This gene-disease relationship has been studied in at least 5 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in MSH2 and breast cancer. Likewise, another two large case-control studies published in 2017 screened breast cancer cases from commercial laboratories and did not find significant association of pathogenic mutations in MSH2 with breast cancer (PMID: 28418444, 35172496). In addition, Slavin et al 2017 (PMID:28649662) showed no significant association of pathogenic MSH2 variant with breast cancer although with large confidence intervals (OR:4.72, 95% CI:0.687-22.8). **Summary of Experimental Data: 1 POINTS** While case control studies did not support the gene-disease association, there is experimental evidence showing that MSH2 physically interacts with estrogen receptors (0.5 point, PMID:15886699). Another study reported negative staining in breast cancer tissues, while normal MSH2 expression was observed in adjacent normal tissues (0.5 point, PMID:30149959). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between MSH2 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 10/11/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0030840
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0005212
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Oncologic
Intervention: Oncologic
Rationale: 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
Comments: Homozygous/compound heterozygous variants have been described in individuals with severe disease; Variants in PMS1 thought to be associated with hereditary colon cancer were found to co-segregate in individuals with MSH2 variants; Variants may also contribute to cancer susceptibility, and individuals may be at risk for a number of cancer types
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MSH2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000251.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 12 | 4 | 21 | 1011 | 103 | 1151 |
| missense | 93 | 182 | 1919 | 1201 | 30 | 3425 |
| nonsense | 329 | 33 | 16 | 378 | ||
| start loss | 13 | 2 | 9 | 24 | ||
| frameshift | 1209 | 136 | 22 | 1367 | ||
| splice donor/acceptor (+/-2bp) | 121 | 178 | 14 | 313 | ||
| Total | 1777 | 535 | 2001 | 2212 | 133 | 6658 |
Highest pathogenic variant AF is 0.002676567
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000242.1 | 16 | MANE Select | |
| Ensembl | ENSP00000233146.2 | 16 | MANE Select | |
| RefSeq | NP_001245210.1 | 16 | Standard | |
| RefSeq | NP_001393560.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| msh2 | Danio rerio | Structure: whole organism Quality: neoplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Doxorubicin Pathway (Cancer Cell), Pharmacodynamics
- Mismatch repair - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Busulfan Pathway, Pharmacodynamics
- Colorectal cancer - Homo sapiens (human)
Biological Process
- in utero embryonic development
- oxidative phosphorylation
- DNA repair
- mismatch repair
- postreplication repair
Molecular Function
- magnesium ion binding
- four-way junction DNA binding
- DNA binding
- chromatin binding
- damaged DNA binding
Cellular Component
- nuclear chromosome, telomeric region
- nucleus
- nucleoplasm
- membrane
- mismatch repair complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000233146
- Coding exons
- 16
- Length
- 159343
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125748
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.45 | 634 | 483 | 1.31 | 0.0000232 | 6133 |
| Missense (PolyPhen) | 188 | 177.96 | 1.0564 | 2257 | ||
| Synonymous | -1.83 | 202 | 172 | 1.18 | 0.00000847 | 1733 |
| Loss of Function | 5.13 | 9 | 47.0 | 0.192 | 0.00000249 | 579 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000061 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00013 | rare |
| South Asian | 0.00040 | 0.00036 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2- MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containg DNA strand (PubMed:26300262). ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. In melanocytes may modulate both UV-B- induced cell cycle regulation and apoptosis. {ECO:0000269|PubMed:10078208, ECO:0000269|PubMed:10660545, ECO:0000269|PubMed:15064730, ECO:0000269|PubMed:17611581, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:26300262, ECO:0000269|PubMed:9564049, ECO:0000269|PubMed:9822679, ECO:0000269|PubMed:9822680}.;
- Disease
- DISEASE: Hereditary non-polyposis colorectal cancer 1 (HNPCC1) [MIM:120435]: 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. HNPCC is reported to be the most common form of inherited colorectal cancer in the Western world. Clinically, HNPCC 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 HNPCC 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 HNPCC' or 'incomplete HNPCC' 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. {ECO:0000269|PubMed:10375096, ECO:0000269|PubMed:10386556, ECO:0000269|PubMed:10528862, ECO:0000269|PubMed:10573010, ECO:0000269|PubMed:10612836, ECO:0000269|PubMed:10777691, ECO:0000269|PubMed:10829038, ECO:0000269|PubMed:11726306, ECO:0000269|PubMed:11870161, ECO:0000269|PubMed:11920458, ECO:0000269|PubMed:12112654, ECO:0000269|PubMed:12124176, ECO:0000269|PubMed:12132870, ECO:0000269|PubMed:12200596, ECO:0000269|PubMed:12362047, ECO:0000269|PubMed:12373605, ECO:0000269|PubMed:12655564, ECO:0000269|PubMed:12655568, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14635101, ECO:0000269|PubMed:15046096, ECO:0000269|PubMed:15300854, ECO:0000269|PubMed:15342696, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:15613555, ECO:0000269|PubMed:15870828, ECO:0000269|PubMed:15896463, ECO:0000269|PubMed:15991316, ECO:0000269|PubMed:15996210, ECO:0000269|PubMed:16451135, ECO:0000269|PubMed:17101317, ECO:0000269|PubMed:17128465, ECO:0000269|PubMed:18561205, ECO:0000269|PubMed:18625694, ECO:0000269|PubMed:18781619, ECO:0000269|PubMed:18822302, ECO:0000269|PubMed:18951462, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22102614, ECO:0000269|PubMed:22371642, ECO:0000269|PubMed:7874129, ECO:0000269|PubMed:8261515, ECO:0000269|PubMed:8700523, ECO:0000269|PubMed:8797773, ECO:0000269|PubMed:8872463, ECO:0000269|PubMed:9048925, ECO:0000269|PubMed:9240418, ECO:0000269|PubMed:9298827, ECO:0000269|PubMed:9311737, ECO:0000269|PubMed:9419403, ECO:0000269|PubMed:9559627, ECO:0000269|PubMed:9621522, ECO:0000269|PubMed:9718327, ECO:0000269|PubMed:9889267}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muir-Torre syndrome (MRTES) [MIM:158320]: Rare autosomal dominant disorder characterized by sebaceous neoplasms and visceral malignancy. {ECO:0000269|PubMed:7713503}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:11306449, ECO:0000305|PubMed:21642682}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, 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. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269|PubMed:12549480, ECO:0000269|PubMed:16372347}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:12792735, ECO:0000269|PubMed:14504054, ECO:0000269|PubMed:15996210, ECO:0000269|PubMed:9559627}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.693
Intolerance Scores
- LoFtool
- 0.00971
- RVIS EVS
- -2.03
- RVIS percentile EVS
- 1.68
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.989
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |