ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1537A>G (p.Ile513Val) (rs746897461)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221108 SCV000278057 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
Invitae RCV000550953 SCV000624663 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 513 of the MSH6 protein (p.Ile513Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs746897461, ExAC 0.001%) but has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233637). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and 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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