ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5770G>A (p.Gly1924Arg)

gnomAD frequency: 0.00002  dbSNP: rs371862779
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235763 SCV000293946 uncertain significance not provided 2023-05-16 criteria provided, single submitter clinical testing 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
Labcorp Genetics (formerly Invitae), Labcorp RCV000235763 SCV000653401 uncertain significance not provided 2024-04-22 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1924 of the POLE protein (p.Gly1924Arg). This variant is present in population databases (rs371862779, gnomAD 0.005%). 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: 246404). 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.
Ambry Genetics RCV002356325 SCV002652097 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-08 criteria provided, single submitter clinical testing The p.G1924R variant (also known as c.5770G>A), located in coding exon 42 of the POLE gene, results from a G to A substitution at nucleotide position 5770. The glycine at codon 1924 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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