Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759239 | SCV000888463 | uncertain significance | not provided | 2018-03-13 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001051386 | SCV001215538 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-08-29 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 991 of the POLD1 protein (p.Cys991Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 619714). 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. 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 | RCV002440586 | SCV002751155 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-28 | criteria provided, single submitter | clinical testing | The p.C991Y variant (also known as c.2972G>A), located in coding exon 23 of the POLD1 gene, results from a G to A substitution at nucleotide position 2972. The cysteine at codon 991 is replaced by tyrosine, an amino acid with highly dissimilar 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479213 | SCV004223736 | uncertain significance | not specified | 2023-11-13 | criteria provided, single submitter | clinical testing | Variant summary: POLD1 c.2972G>A (p.Cys991Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 170720 control chromosomes in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2972G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |