ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3557G>A (p.Gly1186Asp) (rs587781690)

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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 RCV000129855 SCV000184672 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000206364 SCV000260543 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1186 of the MSH6 protein (p.Gly1186Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs587781690, ExAC 0.005%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141364). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000657043 SCV000567381 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3557G>A at the cDNA level, p.Gly1186Asp (G1186D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly1186Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. In addition, multiple splicing models predict that this variant may destroy the nearby natural splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MSH6 Gly1186Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000485699 SCV000712797 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing The p.Gly1186Asp variant in MSH6 has not been previously reported in individuals with Lynch syndrome but has been identified in 3/66564 of European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs587781690). This variant is located in the first base of the exon, which is part of the 3? splice region. Splicing prediction tools do not suggest altered s plicing and computational prediction tools and conservation analysis suggest tha t the p.Gly1186Asp variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, the clinical signifi cance of the p.Gly1186Asp variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657043 SCV000889489 uncertain significance not provided 2018-03-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764433 SCV000895490 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing

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