ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2876G>A (p.Arg959His) (rs757653982)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165726 SCV000216467 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000204562 SCV000261435 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 959 of the MSH6 protein (p.Arg959His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs757653982, ExAC 0.002%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 186181). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506421 SCV000601544 uncertain significance not specified 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000662759 SCV000785553 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-11-14 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000758673 SCV000887444 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.2876G>A has a 92.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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