Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000467594 | SCV000547625 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 426 of the POLD1 protein (p.Gly426Ser). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 408073). 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 | RCV000563063 | SCV000670940 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-15 | criteria provided, single submitter | clinical testing | The p.G426S variant (also known as c.1276G>A), located in coding exon 10 of the POLD1 gene, results from a G to A substitution at nucleotide position 1276. The glycine at codon 426 is replaced by serine, an amino acid with similar properties. This alteration was reported in 1/469 cases with multiple colorectal adenomas and/or familial CRC; however, structural studies showed that this alteration is unlikely to be involved in direct DNA binding, and was predicted to have only moderate functional effects (Palles C et al. Nat. Genet. 2013 Feb;45(2):136-44). This alteration was also identified in an individual diagnosed with colorectal cancer (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32).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 |
RCV003313071 | SCV004012249 | uncertain significance | not provided | 2023-07-31 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individual(s) with colorectal adenomas and/or familial colorectal cancer (Palles et al., 2013; Chubb et al., 2015); This variant is associated with the following publications: (PMID: 25559809, 23263490, 20951805) |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003313071 | SCV004219054 | uncertain significance | not provided | 2023-01-25 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000064 (2/31364 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMIDs: 23263490 (2013), 25559809 (2015)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. |