MSH6
protein-codingmutS homolog 6, the group of PWWP domain containing|MutS homologs
Gene summary
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. [provided by RefSeq, Jul 2013]
- GTBP
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~114.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013710
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008170
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: ClinGen
MSH6 was first reported in relation to autosomal dominant Lynch Syndrome (LS, MONDO:0005835) in 1997 (Miyaki M. et al., PMID: 9354786). Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC), is a cancer predisposition syndrome; LS is caused by pathogenic germline variants (PGV) in DNA mismatch repair (MMR) genes, including MSH6, inherited in an autosomal dominant pattern. Biallelic MSH6 PGVs also cause a distinct mismatch repair deficiency cancer syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we separate these two curations due to different inheritance patterns and phenotype. This curation only focuses on the dominant LS condition. In this curation, we included 14 PGVs, including missense, deletions, nonsense, and duplications that have been reported in multiple patients and families (PMIDs: 9354786, 10521294, 36612224, 11709755, 26805314). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function (LOF). MSH6-Lynch Syndrome association is supported by experimental evidence at a biochemical and functional level (6 points). Drummond JT et al., 1995, (PMID: 7604264) describes the isolation of an MSH2–MSH6 heterodimer that restores DNA mismatch repair to tumor cells; in the same issue, Palombo F, et al., 1995, (PMID: 7604265) reported that the DNA mismatch recognition and binding in human cells has been thought to be mediated by the hMSH2 protein, they showed that the mismatch-binding factor consists of two distinct proteins, the 100-kilodalton hMSH2 and a 160-kilodalton polypeptide, GTBP (for G/T binding protein). Both proteins are required for mismatch-specific binding, a result consistent with the finding that tumor-derived cell lines devoid of either protein are also devoid of mismatch-binding activity. Sequence analysis identified GTBP as a new member of the MutS homolog family. Edelmann W, et al., (PMID: 9390556) also reported that extracts from the Msh6-/- cells were defective for the repair of single nucleotide mismatches. In addition, homozygous mice had a reduced lifespan and developed a spectrum of tumors. The mice showed tumors in the intestine (adenoma), the liver (hepatoma), and B- and T-cell lymphomas. In summary, MSH6 is definitively associated with autosomal dominant inheritance and Lynch Syndrome. This has been repeatedly demonstrated in research and clinical diagnostic settings and upheld over time. This gene-disease pair was initially evaluated by the Colon Cancer Expert Panel on 09/25/2017. It was reevaluated on 03/24/2023 (SOP Version 9). As a result of this reevaluation, the classification did not change.
Inheritance Pattern: AD
Disease ID:MONDO:0007254
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013710
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008018
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0016419
Submitter: ClinGen
*MSH6* encodes a protein playing a key role in the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that occur during DNA replication and homologous recombination. MSH6 heterodimerizes with MSH2 to form a mismatch recognition complex functioning as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. MSH6 has been linked to Lynch Syndrome (autosomal dominant) and mismatch repair cancer syndrome (autosomal recessive), which were curated separately. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, curations to refute or dispute can be split when needed. This curation focuses on disputing the association with breast cancer. Evidence curated in this gene-disease relationship includes case-control data. **Summary of Case-Control Data: 4 points** This gene-disease relationship has been studied in at least 5 case-control or cohort studies at the single or aggregate variant level. There is evidence supporting the gene-disease relationship. BCAC, a large case-control study published in 2021 (PMID: 33471991), showed a significant association with moderate odds ratio (=1.96) of aggregated pathogenic *MSH6* variants with breast cancer (3 point). Another case-control study reported by Lu et al. (PMID: 30128536) also demonstrated a significant association (Odds Ratio=2.59). However, the case population Lu et al. study includes breast cancer and/or ovarian cancer; therefore, the strength of this evidence is limited (1 point). Evidence did not support the gene-disease relationship also reported. In 2021, a large case-control study [CARRIERS (PMID: 33471974) with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in *MSH6* 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 *MSH6* with breast cancer (PMID: 28418444, 35172496). **Overall Summary:** In summary, given that case-control studies show either a modest effect of increased risk, or no increased risk for colorectal cancer in monoallelic *MSH6* variant carriers, the Hereditary Cancer GCEP has disputed this gene-disease association. More evidence is needed to either support or entirely refute the role *MSH6* plays in autosomal dominant breast cancer. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 7/26/2017. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 6/9/2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0030841
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0030841
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0005212
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008315
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: ClinGen
There has been sufficient evidence published associating the MSH6 gene with constitutional mismatch repair deficiency syndrome - a distinct disorder from Lynch syndrome - since the gene-disease relationship was first proposed by Menko, et al., (2004). Multiple case level studies have been performed with cMMRD patients that have variants in the MSH6 gene. Other mismatch repair (MMR) genes MLH1, MSH2 and PMS2 also causes constitutional mismatch repair deficiency syndrome. IHC and western blot revealed absence of MSH6 protein in patient cells. Multiple MSH6 deficient mouse and zebrafish models have been established to show consistent phenotypes with MMRCS patients by developing neurofibromas, non-Hodgkin’s lymphoma (NHL) and gastrointestinal (GI) tumors. All of these types of evidence are consistent with a definitive relationship between the MSH6 gene and constitutional mismatch repair deficiency syndrome.
Inheritance Pattern: AD
Disease ID:MONDO:0013710
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AD
Disease ID:MONDO:0009831
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0030841
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0010159
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0005835
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: 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, 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: Individuals may be at risk for additional types of malignancy
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MSH6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000179.3. 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 | 10 | 4 | 12 | 1652 | 148 | 1826 |
| missense | 68 | 149 | 4405 | 563 | 13 | 5198 |
| nonsense | 431 | 93 | 24 | 3 | 1 | 552 |
| start loss | 8 | 3 | 1 | 12 | ||
| frameshift | 1376 | 260 | 74 | 6 | 2 | 1718 |
| splice donor/acceptor (+/-2bp) | 25 | 107 | 12 | 4 | 1 | 149 |
| Total | 1918 | 616 | 4528 | 2228 | 165 | 9455 |
Highest pathogenic variant AF is 0.000056520264
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000170.1 | 10 | MANE Select | |
| Ensembl | ENSP00000234420.5 | 10 | MANE Select | |
| RefSeq | NP_001268421.1 | 8 | Standard | |
| RefSeq | NP_001268422.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| msh6 | Danio rerio | Structure: whole organism Quality: neoplastic abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mismatch repair - Homo sapiens (human)
- Pathways in cancer - Homo sapiens (human)
- Colorectal cancer - Homo sapiens (human)
- Signaling Pathways in Glioblastoma
- Retinoblastoma (RB) in Cancer
Biological Process
- meiotic mismatch repair
- DNA repair
- pyrimidine dimer repair
- mismatch repair
- mitotic G2 DNA damage checkpoint
Molecular Function
- magnesium ion binding
- four-way junction DNA binding
- chromatin binding
- damaged DNA binding
- double-stranded DNA binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- Golgi apparatus
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000234420
- Coding exons
- 10
- Length
- 114572
- Individuals with no LoFs
- 125294
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 454
- Defined
- 125748
- p
- 0.00181
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.78 | 917 | 709 | 1.29 | 0.0000376 | 8907 |
| Missense (PolyPhen) | 409 | 375.96 | 1.0879 | 4749 | ||
| Synonymous | -6.32 | 384 | 256 | 1.50 | 0.0000127 | 2643 |
| Loss of Function | 4.51 | 18 | 53.6 | 0.336 | 0.00000342 | 666 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0023 | 0.0022 | notable |
| Latino/Admixed American | 0.0025 | 0.0024 | notable |
| Ashkenazi Jewish | 0.0012 | 0.0012 | notable |
| East Asian | 0.0038 | 0.0037 | notable |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0019 | 0.0018 | notable |
| South Asian | 0.0012 | 0.0011 | notable |
| Other | 0.0022 | 0.0021 | notable |
dbNSFP Gene Annotations
Source:
- Function
- 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. {ECO:0000269|PubMed:10078208, ECO:0000269|PubMed:10660545, ECO:0000269|PubMed:15064730, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:9564049, ECO:0000269|PubMed:9822679, ECO:0000269|PubMed:9822680}.;
- Disease
- DISEASE: Hereditary non-polyposis colorectal cancer 5 (HNPCC5) [MIM:614350]: 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:10480359, ECO:0000269|PubMed:10521294, ECO:0000269|PubMed:11586295, ECO:0000269|PubMed:12658575, ECO:0000269|PubMed:14974087, ECO:0000269|PubMed:15365995, ECO:0000269|PubMed:21120944, ECO:0000269|PubMed:22102614, ECO:0000269|PubMed:9354786}. 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:0000269|PubMed:11153917, ECO:0000269|PubMed:14961575}. 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:17557300}. 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:10413423, ECO:0000269|PubMed:10537275, ECO:0000269|PubMed:10699937, ECO:0000269|PubMed:11153917, ECO:0000269|PubMed:11470537, ECO:0000269|PubMed:11709755, ECO:0000269|PubMed:11807791, ECO:0000269|PubMed:12522549, ECO:0000269|PubMed:14520694, ECO:0000269|PubMed:14961575, ECO:0000269|PubMed:15483016, ECO:0000269|PubMed:22102614}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.777
Intolerance Scores
- LoFtool
- 0.0212
- RVIS EVS
- -2.25
- RVIS percentile EVS
- 1.28
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.827
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |