ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1214C>G (p.Ser405Cys) (rs730881790)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160666 SCV000211276 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1214C>G at the cDNA level, p.Ser405Cys (S405C) 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 a germline variant; however, it has been reported as a somatic variant in either a lung or colorectal tumor, as well as a thymus tumor (Garofalo 2016, Sholl 2016). MSH6 Ser405Cys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser405Cys occurs at a position that is not conserved across species and is located in the mismatch binding domain (Warren 2007, Kansikas 2011). 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 Ser405Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195871 SCV000254271 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 405 of the MSH6 protein (p.Ser405Cys). 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: 182621). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Ambry Genetics RCV000563544 SCV000669921 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000780479 SCV000917763 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1214C>G (p.Ser405Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246082 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (8.1e-06 vs 0.00014), allowing no conclusion about variant significance. c.1214C>G has been reported in the literature (Garofalo 2016), however, 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 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000563544 SCV001344149 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing

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