ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.