Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000486951 | SCV000570742 | uncertain significance | not provided | 2016-06-23 | criteria provided, single submitter | clinical testing | This variant is denoted POLD1 c.2338G>T at the cDNA level, p.Asp780Tyr (D780Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLD1 Asp780Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. POLD1 Asp780Tyr occurs at a position that is not conserved and is located in this Polymerase domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether POLD1 Asp780Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV000807773 | SCV000947845 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-07-03 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 421513). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 780 of the POLD1 protein (p.Asp780Tyr). 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 | RCV002446932 | SCV002733008 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-10-30 | criteria provided, single submitter | clinical testing | The p.D780Y variant (also known as c.2338G>T), located in coding exon 18 of the POLD1 gene, results from a G to T substitution at nucleotide position 2338. The aspartic acid at codon 780 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. |