ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6434G>A (p.Arg2145Gln)

gnomAD frequency: 0.00002  dbSNP: rs770009143
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001547671 SCV000543930 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2145 of the POLE protein (p.Arg2145Gln). This variant is present in population databases (rs770009143, gnomAD 0.02%). 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: 405619). 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 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.
GeneDx RCV001547671 SCV001767433 uncertain significance not provided 2023-12-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268063 SCV002550035 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002365608 SCV002657419 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-29 criteria provided, single submitter clinical testing The p.R2145Q variant (also known as c.6434G>A), located in coding exon 46 of the POLE gene, results from a G to A substitution at nucleotide position 6434. The arginine at codon 2145 is replaced by glutamine, 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 RCV002489015 SCV002797722 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 2021-08-23 criteria provided, single submitter clinical testing

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