Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000531499 | SCV000646494 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 525 of the POLD1 protein (p.Arg525Gln). This variant is present in population databases (rs372190244, gnomAD 0.03%). 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: 469207). 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 | RCV001012220 | SCV001172646 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-15 | criteria provided, single submitter | clinical testing | The p.R525Q variant (also known as c.1574G>A), located in coding exon 12 of the POLD1 gene, results from a G to A substitution at nucleotide position 1574. The arginine at codon 525 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not 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. |
| Gene |
RCV001591246 | SCV001823836 | uncertain significance | not provided | 2021-03-29 | criteria provided, single submitter | clinical testing | 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; This variant is associated with the following publications: (PMID: 31857678) |
| Sema4, |
RCV001012220 | SCV002534595 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-26 | criteria provided, single submitter | curation | |
| Fulgent Genetics, |
RCV002491066 | SCV002782583 | uncertain significance | Colorectal cancer, susceptibility to, 10; Mandibular hypoplasia-deafness-progeroid syndrome | 2021-08-31 | criteria provided, single submitter | clinical testing | |
| St. |
RCV000531499 | SCV003928115 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-04-20 | criteria provided, single submitter | clinical testing | The POLD1 c.1574G>A (p.Arg525Gln) missense change has a maximum subpopulation frequency of 0.024% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in tumor(s) with ~10 mutations/Mb (PMID: 29056344). It was reported as somatic in a colorectal carcinoma from a 21-year-old nonsyndromic patient whose tumor also harbored a heterozygous POLE p.V411L mutation (PMID: 31857678). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
| Baylor Genetics | RCV000531499 | SCV004203440 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-10-22 | criteria provided, single submitter | clinical testing |