ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.782C>T (p.Ser261Phe) (rs876661250)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220529 SCV000279894 uncertain significance not provided 2016-02-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.782C>T at the cDNA level, p.Ser261Phe (S261F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser261Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser261Phe occurs at a position that is conserved across species and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ser261Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473051 SCV000551170 uncertain significance Hereditary nonpolyposis colon cancer 2019-09-17 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 261 of the MSH6 protein (p.Ser261Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234838). 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 novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000574186 SCV000662573 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-20 criteria provided, single submitter clinical testing Insufficient evidence

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