Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001209399 | SCV001380831 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-05-30 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 939918). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the POLD1 protein (p.Asp249Asn). |
St. |
RCV001209399 | SCV001775514 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2021-07-29 | criteria provided, single submitter | clinical testing | The POLD1 c.745G>A (p.Asp249Asn) missense change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4. |
Ambry Genetics | RCV002379792 | SCV002670345 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-06-27 | criteria provided, single submitter | clinical testing | The p.D249N variant (also known as c.745G>A), located in coding exon 5 of the POLD1 gene, results from a G to A substitution at nucleotide position 745. The aspartic acid at codon 249 is replaced by asparagine, an amino acid with highly 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. |