ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.944C>G (p.Ser315Cys) (rs63750491)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566795 SCV000662506 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586030 SCV000695935 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.944C>G (p.Ser315Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro and UniProt) and 3/5 in silico tools predict a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant does not affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/121192 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000696871 SCV000825451 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-23 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 315 of the MSH6 protein (p.Ser315Cys). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is present in population databases (rs63750491, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 479920). 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.

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