ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1037C>G (p.Ser346Cys) (rs567785169)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459417 SCV000551291 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-26 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 346 of the MSH6 protein (p.Ser346Cys). The serine residue is weakly 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: 410527). 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 cysteine 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 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.
GeneDx RCV000479642 SCV000571275 uncertain significance not provided 2016-08-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1037C>G at the cDNA level, p.Ser346Cys (S346C) 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 Ser346Cys was not observed at significant allele frequency in the 1000 Genomes. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser346Cys occurs at a position that is not conserved and is located within the N-terminal region as well as a MSH2 binding site (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 Ser346Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562409 SCV000662479 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562409 SCV000908367 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing

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