ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1693G>T (p.Ala565Ser)

dbSNP: rs747247890
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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 RCV003655293 SCV000956548 uncertain significance not provided 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 565 of the POLE protein (p.Ala565Ser). This variant is not present in population databases (gnomAD no frequency). 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: 659112). 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.
Ambry Genetics RCV002406856 SCV002715407 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-04 criteria provided, single submitter clinical testing The p.A565S variant (also known as c.1693G>T), located in coding exon 16 of the POLE gene, results from a G to T substitution at nucleotide position 1693. The alanine at codon 565 is replaced by serine, 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.
Fulgent Genetics, Fulgent Genetics RCV005004447 SCV005633755 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 2024-05-31 criteria provided, single submitter clinical testing

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