ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1724A>G (p.Asp575Gly) (rs370330868)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679295 SCV000149416 uncertain significance not provided 2016-05-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1724A>G at the cDNA level, p.Asp575Gly (D575G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp575Gly was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Asp575Gly occurs at a position that is not conserved across species and is located in the Lever domain and the region of interaction with MSH6 and MSH3 (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 Asp575Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115507 SCV000184571 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000198150 SCV000254390 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 575 of the MSH2 protein (p.Asp575Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs370330868, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127634). 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.
Color RCV000115507 SCV000292185 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679295 SCV000806009 uncertain significance not provided 2017-02-10 criteria provided, single submitter clinical testing
Mendelics RCV000708833 SCV000837836 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.