ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3446C>G (p.Ala1149Gly)

dbSNP: rs778212434
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003151840 SCV001405211 uncertain significance not provided 2023-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1149 of the POLE protein (p.Ala1149Gly). 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: 959322). 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 expected to disrupt POLE protein function. 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 RCV002451554 SCV002617149 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-25 criteria provided, single submitter clinical testing The p.A1149G variant (also known as c.3446C>G), located in coding exon 28 of the POLE gene, results from a C to G substitution at nucleotide position 3446. The alanine at codon 1149 is replaced by glycine, 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.
GeneDx RCV003151840 SCV003840842 uncertain significance not provided 2022-09-13 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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