ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2327A>G (p.Lys776Arg)

gnomAD frequency: 0.00001  dbSNP: rs375791061
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
Labcorp Genetics (formerly Invitae), Labcorp RCV001284045 SCV000543960 uncertain significance not provided 2025-01-30 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 776 of the POLE protein (p.Lys776Arg). This variant is present in population databases (rs375791061, gnomAD 0.0009%). 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: 405649). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001284045 SCV001469619 uncertain significance not provided 2020-05-29 criteria provided, single submitter clinical testing
GeneDx RCV001284045 SCV001768523 uncertain significance not provided 2023-12-24 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805)
Ambry Genetics RCV003168747 SCV003896320 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-11 criteria provided, single submitter clinical testing The p.K776R variant (also known as c.2327A>G), located in coding exon 21 of the POLE gene, results from an A to G substitution at nucleotide position 2327. The lysine at codon 776 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005010339 SCV005633741 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 2024-01-02 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.