ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5662G>A (p.Glu1888Lys)

gnomAD frequency: 0.00004  dbSNP: rs368363850
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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 RCV000484064 SCV000543967 uncertain significance not provided 2025-01-12 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 1888 of the POLE protein (p.Glu1888Lys). This variant is present in population databases (rs368363850, 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: 405655). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 RCV000484064 SCV000572619 uncertain significance not provided 2024-12-03 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484064 SCV001134741 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002489016 SCV002781189 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 2021-07-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168748 SCV003892470 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-05 criteria provided, single submitter clinical testing The p.E1888K variant (also known as c.5662G>A), located in coding exon 41 of the POLE gene, results from a G to A substitution at nucleotide position 5662. The glutamic acid at codon 1888 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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