Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000563591 | SCV000671189 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-01 | criteria provided, single submitter | clinical testing | The p.M535I variant (also known as c.1605G>C), located in coding exon 12 of the POLD1 gene, results from a G to C substitution at nucleotide position 1605. The methionine at codon 535 is replaced by isoleucine, an amino acid with highly similar properties. 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 | RCV001858338 | SCV002210789 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-12-24 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 535 of the POLD1 protein (p.Met535Ile). 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: 484416). 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. |
| Baylor Genetics | RCV001858338 | SCV004203490 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-07-06 | criteria provided, single submitter | clinical testing |