ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1390A>T (p.Ile464Phe) (rs201892477)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217580 SCV000278050 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034491 SCV000043354 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Invitae RCV000231596 SCV000283712 uncertain significance Hereditary nonpolyposis colon cancer 2017-02-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 464 of the MSH6 protein (p.Ile464Phe). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 41587). 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 variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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