ClinVar Miner

Submissions for variant NM_002691.4(POLD1):c.1294C>T (p.Arg432Trp)

gnomAD frequency: 0.00003  dbSNP: rs774130423
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475830 SCV000547623 uncertain significance Colorectal cancer, susceptibility to, 10 2023-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 432 of the POLD1 protein (p.Arg432Trp). This variant is present in population databases (rs774130423, gnomAD 0.01%). 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: 408071). 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 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.
Ambry Genetics RCV001010806 SCV001171055 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-30 criteria provided, single submitter clinical testing The p.R432W variant (also known as c.1294C>T), located in coding exon 10 of the POLD1 gene, results from a C to T substitution at nucleotide position 1294. The arginine at codon 432 is replaced by tryptophan, an amino acid with 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.
Sema4, Sema4 RCV001010806 SCV002534577 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-26 criteria provided, single submitter curation

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