ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4270G>A (p.Glu1424Lys)

gnomAD frequency: 0.00002  dbSNP: rs575419120
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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 RCV000985977 SCV000544010 uncertain significance not provided 2024-01-16 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 1424 of the POLE protein (p.Glu1424Lys). This variant is present in population databases (rs575419120, gnomAD 0.006%). 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: 405695). 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.
Fulgent Genetics, Fulgent Genetics RCV000765058 SCV000896255 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-10-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985977 SCV001134725 uncertain significance not provided 2019-07-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002329028 SCV002629978 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-04 criteria provided, single submitter clinical testing The p.E1424K variant (also known as c.4270G>A), located in coding exon 33 of the POLE gene, results from a G to A substitution at nucleotide position 4270. The glutamic acid at codon 1424 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 RCV005004166 SCV005633701 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 2024-05-07 criteria provided, single submitter clinical testing

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