ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1081C>T (p.Arg361Cys) (rs587782651)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132064 SCV000187127 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000230863 SCV000283700 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 361 of the MSH6 protein (p.Arg361Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine 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: 142698). 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 RCV000132064 SCV000690171 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589862 SCV000695774 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1081C>T (p.Arg361Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has not been found in a large, broad control population, ExAC in 121308 control chromosomes but was reported in 13/245822 control chromosomes in gnomAD at a frequency of 0.00005288, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor 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).
University of Washington Department of Laboratory Medicine, University of Washington RCV000758606 SCV000887360 likely benign Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1081C>T has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589862 SCV000889453 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing

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