MSH6
  • 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
MSH6 (HGNC:7329) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
mutS homolog 6
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
GTBP
Alias symbols
MSH-6
%HI
6.24(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
0.84(Read more about gnomAD LOEUF score)
Cytoband
2p16.3
Genomic Coordinates
GRCh37/hg19: chr2:48010284-48034092 NCBI Ensembl UCSC
GRCh38/hg38: chr2:47783145-47810101 NCBI Ensembl UCSC
MANE Select Transcript
NM_000179.3 ENST00000234420.11 (Read more about MANE Select)
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 downstrea... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-11315
ClinGen Curation ID:
CCID:007485
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Read full report...
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Read full report...
Assoc. with Reduced Penetrance:
Yes
Last Evaluated:
10/13/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Colorectal cancer, hereditary nonpolyposis, type 5 Monarch
HI Evidence:
  • PUBMED: 9354786
    Miyaki et al. (1997). This is one of the earliest reports suggest that germline LOF variant of MSH6 causes Hereditary nonpolyposis colorectal cancer (HNPCC). A Japanese HNPCC family with a germline frameshift variant c.534delC in the MSH6 gene, segregating with four affected family members.
  • PUBMED: 11709755
    Berends et al. (2002) analyzed 316 individuals who were known or suspected to have HNPCC analyzed for MSH6 germline variants. Five truncating MSH6 variants, of which one was detected seven times, were found in 12 index patients, including c.650insT, c.3263insT, p.Gln1258Ter, p.2672delT, p.Gln1280Ter.
  • PUBMED: 14974087
    Plaschke et al 2004 identifies 7 truncating variants in MSH6 associated with tumors displaying high levels of micro satellite instability. The LOF variants include two nonsense variants (c.426G>A [p.W142X], c.2105C>A [p.S702X]), two insertions (c.2611_2614dupATTA [p.I872fsX10], c.3324dupT [p.I1109fsX3]) and three deletions (c.1190_1191delAT [p.Y397fsX3], c.1632_1635delAAAA [p.E544fsX26], c.3513_3514delTA [p.1171fsX5]).
  • PUBMED: 20028993
    Baglietto et al (2010) assess the risk of Lynch syndrome in 113 MSH6 variant carriers, including 50 frameshift variants, 11 nonsense variants, and two exon-level deletions collected from multiple cancer centers. Compared with incidence for the general population, MSH6 variant carriers had an eightfold increased incidence of colorectal cancer, which was independent of sex and age. Women who were MSH6 variant carriers had a 26-fold increased incidence of endometrial cancer and a 6-fold increased incidence of other cancers associated with Lynch syndrome.
  • PUBMED: 20487569
    Talseth-Palmer et al (2010) report multiple MSH6 variants in a large cohort of Lynch syndrome families. A total of 78 participants (from 29 families) with a variant in MSH6, including 17 frameshift variants and 3 nonsense variants.
  • PUBMED: 25318681
    Castellsague et al. (2015) identified a heterozygous c.10C>T transition in the MSH6 gene, resulting in p.Q4X nonsense variant in a family of 11 probands of French Canadian descent with hereditary nonpolyposis colorectal cancer, type 5 (HNPCC5; 614350). Analysis of 27 additional family members indicated that the variant cosegregated with cancer in 15 of 23 carriers, consistent with incomplete penetrance. Heterozygous carriers had an average age of cancer diagnosis at 44.2 years; 1 homozygous carrier had onset at age 10 years. All evaluable tumors showed loss of MSH6 protein and microsatellite instability (MSI).
HI Evidence Comments:
Gene Reviews (http://www.ncbi.nlm.nih.gov/books/NBK1211/) estimates ~7-10% Lynch Syndrome subjects have germline variants in MSH6 (deletions, frameshift, stops) that cause loss of MSH6. Throughout literature this estimate is repeated. While the mechanism is not explicit, overall it is thought heterozygous variants in MSH6 impair mismatch repair. From Bellizzi et al (2009, PMID:19851131): "The MMR proteins function as heterodimers. The MSH2-MSH6 complex recognizes mispaired bases and insertion/deletion loops. It recruits MLH1-PMS2, which subsequently directs the remainder of the MMR machinery. MSH2 and MLH1 are the dominant (obligate) constituents of their respective pairs. In the absence of MSH6, MSH2 can pair with MSH3, and in the absence of PMS2, MLH1 can pair with PMS1. This may partially explain the somewhat attenuated Lynch phenotype attributed to MSH6 and PMS2 mutation, (reduced penetrance and older age of onset relative to MSH2 and MLH1 mutants…)"

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
At this time there is no evidence for triplosensitivity in this gene.

Genomic View

Select assembly: (NC_000002.11) (NC_000002.12)