ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.964C>T (p.Arg322Cys)

gnomAD frequency: 0.00001  dbSNP: rs750155990
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000474306 SCV000547614 uncertain significance Colorectal cancer, susceptibility to, 10 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 322 of the POLD1 protein (p.Arg322Cys). This variant is present in population databases (rs750155990, gnomAD 0.02%). 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: 408062). 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 POLD1 protein function with a positive 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.
Ambry Genetics RCV000573519 SCV000674267 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-16 criteria provided, single submitter clinical testing The p.R322C variant (also known as c.964C>T), located in coding exon 7 of the POLD1 gene, results from a C to T substitution at nucleotide position 964. The arginine at codon 322 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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 RCV003477951 SCV004219066 uncertain significance not provided 2022-10-28 criteria provided, single submitter clinical testing To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.0002 (6/29632 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. 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.

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