ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6511A>G (p.Lys2171Glu)

gnomAD frequency: 0.00001  dbSNP: rs760678210
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001811491 SCV000945142 uncertain significance not provided 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2171 of the POLE protein (p.Lys2171Glu). This variant is present in population databases (rs760678210, gnomAD 0.003%). 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: 650104). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001811491 SCV002049466 uncertain significance not provided 2020-10-31 criteria provided, single submitter clinical testing The POLE c.6511A>G; p.Lys2171Glu variant (rs760678210), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 650104). This variant is found in the general population with an overall allele frequency of 0.001% (3/235,440 alleles) in the Genome Aggregation Database. This variant is not located in the exonuclease domain of POLE (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). Due to limited information, the clinical significance of the p.Lys2171Glu variant is uncertain at this time.
GeneDx RCV001811491 SCV005688476 uncertain significance not provided 2024-07-30 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: 19296856)

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