ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2020G>A (p.Glu674Lys)

gnomAD frequency: 0.00001  dbSNP: rs779458859
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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 RCV003655159 SCV000772560 uncertain significance not provided 2024-11-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 674 of the POLE protein (p.Glu674Lys). This variant is present in population databases (rs779458859, gnomAD 0.007%). 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: 540617). 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 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 RCV002422396 SCV002723764 uncertain significance Hereditary cancer-predisposing syndrome 2022-07-26 criteria provided, single submitter clinical testing The p.E674K variant (also known as c.2020G>A), located in coding exon 18 of the POLE gene, results from a G to A substitution at nucleotide position 2020. The glutamic acid at codon 674 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002485466 SCV002780564 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 2022-01-13 criteria provided, single submitter clinical testing

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