ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2770C>T (p.Arg924Cys)

gnomAD frequency: 0.00004  dbSNP: rs369751686
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000759994 SCV000543901 uncertain significance not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 924 of the POLE protein (p.Arg924Cys). This variant is present in population databases (rs369751686, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405595). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. 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 RCV000759994 SCV000889734 uncertain significance not provided 2018-02-03 criteria provided, single submitter clinical testing
GeneDx RCV000759994 SCV001825990 uncertain significance not provided 2025-01-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in an individual with small bowel cancer whose tumor was microsatellite unstable and demonstrated loss of MSH2 and MSH6 expression, but also harbored two somatic MSH2 missense variants (PMID: 29987844); This variant is associated with the following publications: (PMID: 25801821, 36497424, 29987844, 20951805, 34326862)
Fulgent Genetics, Fulgent Genetics RCV002481392 SCV002780174 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2021-07-22 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.