ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4012G>A (p.Glu1338Lys)

gnomAD frequency: 0.00001  dbSNP: rs751555395
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001569979 SCV000544135 uncertain significance not provided 2024-11-11 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 1338 of the POLE protein (p.Glu1338Lys). This variant is present in population databases (rs751555395, 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: 405810). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000608100 SCV000712815 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing The p.Glu1338Lys variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/11246 of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs751555395). Computational prediction tools and conservation analysis sugges t that the p.Glu1338Lys variant may not impact the protein, though this informat ion is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu1338Lys variant is uncertain.
GeneDx RCV001569979 SCV001794162 uncertain significance not provided 2023-02-21 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002356661 SCV002622199 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-18 criteria provided, single submitter clinical testing The p.E1338K variant (also known as c.4012G>A), located in coding exon 32 of the POLE gene, results from a G to A substitution at nucleotide position 4012. The glutamic acid at codon 1338 is replaced by lysine, an amino acid with 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.

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