ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
14974087 Plaschke et al 2004 identifies 7 truncating mutations in MSH6 associated with tumors displaying high levels of micro satellite instability.
2815724 Baglietto et al (2010) assess the risk of Lynch syndrome in 113 MSH6 mutation carriers (truncation, loss, frameshift indel, or missense damaging) collected from multiple cancer centers. "For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI]?=?14% to 32%) and 44% (95% CI?=?28% to 62%) for men and 10% (95% CI?=?5% to 17%) and 20% (95% CI?=?11% to 35%) for women; for endometrial cancer, 26% (95% CI?=?18% to 36%) and 44% (95% CI?=?30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI?=?16% to 37%) and 47% (95% CI?=?32% to 66%) for men and 40% (95% CI?=?32% to 52%) and 65% (95% CI?=?53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR?=?7.6, 95% CI?=?5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR?=?25.5, 95% CI?=?16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR?=?6.0, 95% CI?=?3.4 to 10.7)."
20487569 Talseth-Palmer et al (2010) report multiple MSH6 mutations in a large cohort of Lynch syndrome families.

Haploinsufficiency phenotype comments:

Gene Reviews ( estimates ~7-10% Lynch Syndrome subjects have germline mutation 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 mutations 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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence for triplosensitivity in this gene.