ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.926A>G (p.Asn309Ser)

gnomAD frequency: 0.00008  dbSNP: rs767060387
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000986000 SCV000544098 uncertain significance not provided 2024-12-06 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 309 of the POLE protein (p.Asn309Ser). This variant is present in population databases (rs767060387, gnomAD 0.008%). 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: 405777). 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 expected to disrupt POLE protein function with a positive 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 RCV000573156 SCV000671437 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-14 criteria provided, single submitter clinical testing The p.N309S variant (also known as c.926A>G), located in coding exon 10 of the POLE gene, results from an A to G substitution at nucleotide position 926. The asparagine at codon 309 is replaced by serine, an amino acid with highly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986000 SCV001134766 uncertain significance not provided 2024-12-03 criteria provided, single submitter clinical testing The POLE c.926A>G (p.Asn309Ser) variant has been reported in the published literature in an individual considered high risk of breast and/or ovarian cancer (PMID: 38874686 (2024)). The frequency of this variant in the general population, 0.0000071 (2/281964 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics RCV000466621 SCV001138899 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV000986000 SCV002107373 uncertain significance not provided 2024-10-02 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; In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805)
Sema4, Sema4 RCV000573156 SCV002536954 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-23 criteria provided, single submitter curation
Baylor Genetics RCV000466621 SCV004203520 uncertain significance Colorectal cancer, susceptibility to, 12 2023-10-10 criteria provided, single submitter clinical testing

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