ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1691T>G (p.Met564Arg)

gnomAD frequency: 0.00001  dbSNP: rs748444470
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506717 SCV000601885 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000544407 SCV000646501 uncertain significance Colorectal cancer, susceptibility to, 10 2025-01-20 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 564 of the POLD1 protein (p.Met564Arg). This variant is present in population databases (rs748444470, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 439253). 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 POLD1 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 RCV001755752 SCV001987431 uncertain significance not provided 2021-10-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000506717 SCV002551930 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV002413387 SCV002715389 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-02 criteria provided, single submitter clinical testing The p.M564R variant (also known as c.1691T>G), located in coding exon 13 of the POLD1 gene, results from a T to G substitution at nucleotide position 1691. The methionine at codon 564 is replaced by arginine, 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.

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