ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1027A>G (p.Asn343Asp) (rs587779961)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115492 SCV000149401 uncertain significance not provided 2016-05-27 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1027A>G at the cDNA level, p.Asn343Asp (N343D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asn343Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Asn343Asp occurs at a position that is not conserved and is located in within the Lever domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Asn343Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000467692 SCV000548223 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 343 of the MSH2 protein (p.Asn343Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127625). 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 tolerated, 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.
Ambry Genetics RCV000562717 SCV000669743 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000562717 SCV000911922 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing

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