ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5270G>T (p.Ser1757Ile)

gnomAD frequency: 0.00001  dbSNP: rs878854882
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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 RCV001568555 SCV000289419 uncertain significance not provided 2023-12-18 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1757 of the POLE protein (p.Ser1757Ile). 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: 240555). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000600769 SCV000731466 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing The p.Ser1757Ile variant in POLE has not been previously reported in the literat ure, but has been reported in ClinVar (Variation ID 240555). This variant was ab sent from large population studies. Computational prediction tools and conservat ion analysis suggest that the p.Ser1757Ile variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, the clinical significance of the p.Ser1757Ile variant is uncertain.
GeneDx RCV001568555 SCV001792448 uncertain significance not provided 2024-06-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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

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