ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2899A>G (p.Ile967Val) (rs876661067)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657064 SCV000279446 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2899A>G at the cDNA level, p.Ile967Val (I967V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile967Val was not observed in large population cohorts (Lek 2016). This variant is located in the clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Ile967Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461768 SCV000551154 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-09-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 967 of the MSH6 protein (p.Ile967Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234533). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214691 SCV000601545 uncertain significance not specified 2016-12-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573070 SCV000670023 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-11 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)

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