ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1376C>G (p.Ser459Cys) (rs587782346)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131285 SCV000186255 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
GeneDx RCV000479474 SCV000571856 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1376C>G at the cDNA level, p.Ser459Cys (S459C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser459Cys 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 Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser459Cys occurs at a position that is conserved across species and is located in the binding sites of MSH2 and the MutS domain I (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ser459Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000548616 SCV000624644 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 459 of the MSH6 protein (p.Ser459Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine 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: 142264). 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.
Color RCV000131285 SCV000685189 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-07 criteria provided, single submitter clinical testing

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