ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1571G>T (p.Arg524Leu) (rs63751207)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165745 SCV000216488 uncertain significance Hereditary cancer-predisposing syndrome 2014-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000165745 SCV000684948 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Invitae RCV000813236 SCV000953587 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 524 of the MSH2 protein (p.Arg524Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Lynch syndrome (PMID: 18931482). ClinVar contains an entry for this variant (Variation ID: 90701). 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. Furthermore, algorithms developed specifically for the MSH2 gene suggest that this missense change is likely to be deleterious (PMID: 24362816, 22290698). However, these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Variants that disrupt the p.524 amino acid residue in MSH2 have been observed in affected individuals (PMID: 7937795, 15849733, 18931482, 26845104). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

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.