ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1402C>T (p.Arg468Cys) (rs369456858)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166488 SCV000217287 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524109 SCV000259967 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 468 of the MSH6 protein (p.Arg468Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs369456858, ExAC 0.001%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 89191). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be disruptive. However, these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000587141 SCV000279094 uncertain significance not provided 2018-04-15 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1402C>T at the cDNA level, p.Arg468Cys (R468C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in at least one individual with a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). MSH6 Arg468Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (Warran 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg468Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166488 SCV000690197 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587141 SCV000695781 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1402C>T (p.Arg468Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121314 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). This variant has been reported in a pt with suspected LS without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222213 SCV000712803 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing The p.Arg468Cys variant in MSH6 has been reported in one individual with suspect ed Lynch syndrome (Yurgelun 2015). This variant has been identified in 1/66704 E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad; dbSNP rs369456858). Computational prediction tools and conservati on analysis suggest that the p.Arg468Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In additio n, this variant has been classified as a variant of uncertain significance on Se ptember 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV0001078 55.2). In summary, the clinical significance of the p.Arg468Cys variant is uncer tain.
PreventionGenetics,PreventionGenetics RCV000587141 SCV000805842 uncertain significance not provided 2017-07-27 criteria provided, single submitter clinical testing
GeneKor MSA RCV000166488 SCV000822059 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000074653 SCV000887366 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1402C>T has a 64.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.20 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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