Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000234504 | SCV000287631 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 157 of the POLD1 protein (p.Gly157Arg). This variant is present in population databases (rs774568050, 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: 239349). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 | RCV000561390 | SCV000671011 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-22 | criteria provided, single submitter | clinical testing | The p.G157R variant (also known as c.469G>A), located in coding exon 4 of the POLD1 gene, results from a G to A substitution at nucleotide position 469. The glycine at codon 157 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 p.G157R remains unclear. |
| Counsyl | RCV000234504 | SCV000786173 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2018-03-19 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759241 | SCV000888465 | uncertain significance | not provided | 2019-06-07 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000759241 | SCV001767680 | uncertain significance | not provided | 2023-01-23 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. |