Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000565011 | SCV000674277 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-06 | criteria provided, single submitter | clinical testing | The p.R444Q variant (also known as c.1331G>A), located in coding exon 10 of the POLD1 gene, results from a G to A substitution at nucleotide position 1331. The arginine at codon 444 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in a cohort of individuals with colorectal cancer (Buchanan DD et al. Genet Med 2018 08;20(8):890-895). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000645847 | SCV000767602 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-28 | 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 444 of the POLD1 protein (p.Arg444Gln). This variant is not present in population databases (gnomAD no frequency). 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: 486061). 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. |
| Gene |
RCV001785665 | SCV002028105 | uncertain significance | not provided | 2021-05-18 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Baylor Genetics | RCV000645847 | SCV004203449 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-10-10 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001785665 | SCV004219057 | uncertain significance | not provided | 2023-02-09 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.0000088 (1/113666 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with colorectal cancer (PMID: 29120461 (2018)). 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. |