MSH6 Gene: Mismatch Repair Protein, Key in Lynch Syndrome and Cancer Susceptibility
Comprehensive genomic and clinical overview of MSH6, a critical DNA mismatch repair gene.
Gene Information Card
| Symbol | MSH6 |
|---|---|
| Full Name | mutS homolog 6 |
| Gene Type | protein-coding |
| Chromosomal Location | 2p16.3 |
| NCBI Gene ID | 2956 ncbi.nlm.nih.gov/gene/2956 |
| Ensembl ID | ENSG00000116062 |
| UniProt ID | P52701 |
| OMIM ID | 600678 |
| HGNC ID | 7329 |
| Aliases | GTBP, GTMBP, HNPCC5, HSAP, MUTS-alpha 160 kDa subunit, p160 |
Description
MSH6 encodes a 160 kDa protein that is a component of the DNA mismatch repair (MMR) system. It forms a heterodimer with MSH2 (MutSα) to recognize base-base mismatches and small insertion-deletion loops during DNA replication. Loss-of-function mutations in MSH6 cause Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) and increase risk for endometrial, ovarian, gastric, and other cancers. MSH6 deficiency leads to microsatellite instability (MSI) and a hypermutator phenotype.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Lynch syndrome (Hereditary non-polyposis colorectal cancer) | Germline loss-of-function mutations in MSH6 impair mismatch repair, leading to accumulation of replication errors and microsatellite instability. | ClinVar, OMIM #600678 |
| Endometrial cancer | MSH6 germline mutations confer high lifetime risk (up to 44-71%) for endometrial cancer, often with MSI-high phenotype. | ClinVar, OMIM #600678 |
| Colorectal cancer (MSI-high) | Somatic or germline MSH6 inactivation causes microsatellite instability, a hallmark of MSI-high colorectal cancers. | COSMIC, ClinVar |
| Ovarian cancer | MSH6 mutations are associated with increased risk of ovarian cancer, particularly endometrioid and clear cell subtypes. | ClinVar, OMIM #600678 |
| Sebaceous neoplasms (Muir-Torre syndrome variant) | MSH6 germline mutations can present with sebaceous tumors as part of Lynch syndrome spectrum. | ClinVar, OMIM #600678 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 38.2 | High |
| Colon | 25.1 | Medium |
| Endometrium | 22.8 | Medium |
| Ovary | 18.5 | Medium |
| Stomach | 16.3 | Medium |
| Brain (cerebellum) | 8.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical carcinoma) | 32.5 | High expression; used in MMR functional assays |
| HCT116 (colorectal carcinoma) | 0.2 | MSH6 null due to frameshift mutation; MSI-high model |
| SW480 (colorectal adenocarcinoma) | 18.7 | Moderate expression; MMR-proficient |
| MCF7 (breast adenocarcinoma) | 14.3 | Moderate expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.3261dupC (p.Phe1088Leufs*5) | Frameshift | Common in Lynch syndrome | Loss of function; truncated protein |
| c.3959_3962delCAAG (p.Thr1320Ilefs*6) | Frameshift | Recurring in endometrial cancer | Loss of function; premature stop |
| c.2633T>C (p.Leu878Pro) | Missense | Rare; pathogenic in Lynch syndrome | Disrupts MSH2 interaction; loss of MMR activity |
| c.3438+1G>A | Splice site | Reported in colorectal cancer | Exon skipping; loss of function |
| p.Tyr1088* | Nonsense | Sporadic in MSI-high tumors | Loss of function; protein truncation |
Mutation functional classification
Loss of Function (LOF)
Most MSH6 pathogenic mutations are loss-of-function (frameshift, nonsense, splice site, large deletions) that abolish MMR activity, leading to MSI and cancer predisposition.
Gain of Function (GOF)
No gain-of-function mutations have been reported for MSH6; the gene acts as a tumor suppressor.
Dominant Negative (DN)
Rare missense mutations (e.g., p.Leu878Pro) may exert dominant-negative effects by disrupting MSH2 binding and impairing the remaining wild-type allele function.
View complete mutation data：
Gene Ontology (GO)
| • GO:0005524 - ATP binding | • GO:0006298 - mismatch repair |
| • GO:0030983 - mismatched DNA binding | • GO:0003684 - damaged DNA binding |
| • GO:0005737 - cytoplasm | • GO:0005634 - nucleus |
| • GO:0006281 - DNA repair | • GO:0016446 - somatic hypermutation of immunoglobulin genes |
Pathways
• Mismatch repair (MMR) pathway (KEGG: hsa03430)
• Colorectal cancer pathway (KEGG: hsa05210)
• Microsatellite instability (MSI) pathway
• DNA damage response (Reactome: R-HSA-73894)
Protein Summary
MSH6 (MutS homolog 6) is a 1360-amino-acid protein that functions as the mismatch recognition subunit of the MutSα heterodimer (MSH2-MSH6). It binds to base-base mismatches and small insertion-deletion loops, initiating the MMR cascade. The protein contains an ATPase domain essential for sliding clamp formation and signal transduction. MSH6 is ubiquitously expressed, with highest levels in testis and colon. Loss of MSH6 function is a hallmark of Lynch syndrome and sporadic MSI-high cancers.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MSH6 Knockout HEK293 Cell Line | EDC07576 | Human | 2956 | Details Get a Quote |
| MSH6 Knockout A-549 Cell Line | EDJ-KQ27584 | Human | 2956 | Details Get a Quote |
| MSH6 Knockout HCT 116 Cell Line | EDJ-KQ27585 | Human | 2956 | Details Get a Quote |
| MSH6 Knockout HeLa Cell Line | EDJ-KQ27586 | Human | 2956 | Details Get a Quote |
| MSH6 Knockout HAP1 Cell Line | EDC08123 | Human | 2956 | Details Get a Quote |
| MSH6 (p.S144I) Point Mutation in HAP1 Cell Line | EDC03555 | Human | 2956 | Details Get a Quote |
| MSH6 (p.F933) Point Mutation in HAP1 Cell Line | EDC03556 | Human | 2956 | Details Get a Quote |
| MSH6 (c.261-36A>G )Point Mutation in HAP1 Cell Line | EDC03554 | Human | 2956 | Details Get a Quote |
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