ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1937A>G (p.Asp646Gly) (rs41295290)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567358 SCV000673894 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000500640 SCV000592525 uncertain significance Lynch syndrome 2012-12-03 criteria provided, single submitter clinical testing
Invitae RCV000553478 SCV000625332 uncertain significance Hereditary nonpolyposis colon cancer 2017-11-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 646 of the MSH2 protein (p.Asp646Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with colon cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 433892). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506889 SCV000601447 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing

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