ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2141C>G (p.Ser714Cys) (rs730881796)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212658 SCV000211291 uncertain significance not provided 2014-07-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2141C>G at the cDNA level, p.Ser714Cys (S714C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). MSH6 Ser714Cys was observed in an individual with adrenocortical carcinoma with a family history of early onset colon cancer (Raymond 2013). MSH6 Ser714Cys 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 Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser714Cys occurs at a position that is conserved across species and is located in the MutS domain II (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Ser714Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160678 SCV000217135 likely benign Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing In silico models in agreement (benign);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Invitae RCV000542696 SCV000624728 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 714 of the MSH6 protein (p.Ser714Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs730881796, ExAC 0.003%). This variant has been reported in an individual with adrenocortical carcinoma (PMID: 23752102). ClinVar contains an entry for this variant (Variation ID: 182633). 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: "Tolerated"; PolyPhen-2: "Possibly 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 RCV000160678 SCV000690244 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174633 SCV001337841 uncertain significance not specified 2020-01-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2141C>G (p.Ser714Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250934 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2141C>G has been reported in the literature in at least one individual affected with adrenocortical carcinoma (Raymond_2013). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x VUS, 1x likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.

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