ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.991C>T (p.Pro331Ser)

dbSNP: rs994360398
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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 RCV001760269 SCV001414766 uncertain significance not provided 2024-12-11 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 331 of the POLE protein (p.Pro331Ser). This variant is present in population databases (no rsID available, 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: 966933). 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.
GeneDx RCV001760269 SCV001989672 uncertain significance not provided 2019-08-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002379927 SCV002691018 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-08 criteria provided, single submitter clinical testing The p.P331S variant (also known as c.991C>T), located in coding exon 10 of the POLE gene, results from a C to T substitution at nucleotide position 991. The proline at codon 331 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. 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.
PreventionGenetics, part of Exact Sciences RCV004528435 SCV004105593 uncertain significance POLE-related disorder 2023-07-13 criteria provided, single submitter clinical testing The POLE c.991C>T variant is predicted to result in the amino acid substitution p.Pro331Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in one allele from the "other" continental population in gnomAD (http://gnomad.broadinstitute.org/variant/12-133252709-G-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/966933/). 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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