ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2009C>T (p.Pro670Leu) (rs41294982)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524371 SCV000259265 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 670 of the MSH2 protein (p.Pro670Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs41294982, ExAC 0.002%). This variant has been reported in a patient with colon cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90855). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and an algorithm developed specifically for the MSH2 gene (PMID: 22290698) all suggest that this missense change is likely to be disruptive, although these predictions have not been confirmed by published functional 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.
Ambry Genetics RCV000220086 SCV000275632 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000483333 SCV000565199 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2009C>T at the cDNA level, p.Pro670Leu (P670L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant has been reported a colorectal cancer patient whose tumor demonstrated microsatellite stability and presence of the MLH1, MSH2, and MSH6 proteins (Barnetson 2008). MSH2 Pro670Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain and the region of interaction with EXO1 (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Pro670Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220086 SCV000690040 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765672 SCV000897014 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 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.