Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000538343 | SCV000646466 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-30 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 402 of the POLD1 protein (p.Asp402Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 469183). 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 | RCV000568783 | SCV000671067 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-12-16 | criteria provided, single submitter | clinical testing | The p.D402N variant (also known as c.1204G>A), located in coding exon 9 of the POLD1 gene, results from a G to A substitution at nucleotide position 1204. The aspartic acid at codon 402 is replaced by asparagine, an amino acid with highly similar properties. In one study that used a yeast-based assay, this alteration was found to cause a strong mutator phenotype (Murphy K et al. Genome, 2006 Apr;49:403-10). 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 | RCV001284039 | SCV001469613 | uncertain significance | not provided | 2020-03-20 | criteria provided, single submitter | clinical testing |