ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1214C>G (p.Ser405Cys)

gnomAD frequency: 0.00001  dbSNP: rs730881790
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160666 SCV000211276 uncertain significance not provided 2023-08-07 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27460824, 27882345, 17531815, 21120944)
Invitae RCV000195871 SCV000254271 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563544 SCV000669921 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-15 criteria provided, single submitter clinical testing The p.S405C variant (also known as c.1214C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1214. The serine at codon 405 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Diagnostics, LLC DBA Color Health RCV000563544 SCV001344149 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-07 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003998492 SCV004835364 uncertain significance Lynch syndrome 2023-11-28 criteria provided, single submitter clinical testing

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