ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3223A>T (p.Ser1075Cys)

gnomAD frequency: 0.00001  dbSNP: rs145680387
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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 RCV001584133 SCV000543921 uncertain significance not provided 2025-01-19 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1075 of the POLE protein (p.Ser1075Cys). 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: 405611). 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 RCV000613961 SCV000731331 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Ser1075Cys variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs145680387). Computational prediction tools and conservation analys is suggest that the p.Ser1075Cys variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Ser1075Cys variant is uncertain.
GeneDx RCV001584133 SCV001820631 uncertain significance not provided 2024-05-31 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; 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; This variant is associated with the following publications: (PMID: 31034466)
PreventionGenetics, part of Exact Sciences RCV004737496 SCV005353632 uncertain significance POLE-related disorder 2024-08-23 no assertion criteria provided clinical testing The POLE c.3223A>T variant is predicted to result in the amino acid substitution p.Ser1075Cys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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