ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1382T>G (p.Phe461Cys) (rs1064793187)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000477991 SCV000565215 uncertain significance not provided 2015-01-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1382T>G at the cDNA level, p.Phe461Cys (F461C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe461Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Phenylalanine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Phe461Cys occurs at a position that is highly conserved across species and is located in the binding sites of MSH2 (Kariola 2002). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider MSH6 Phe461Cys to be a variant of uncertain significance.
Ambry Genetics RCV000564326 SCV000670107 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000815191 SCV000955639 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 461 of the MSH6 protein (p.Phe461Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. 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: 418323). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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