Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236124 | SCV000293597 | uncertain significance | not provided | 2015-11-23 | criteria provided, single submitter | clinical testing | This variant is denoted POLD1 c.2704G>C at the cDNA level, p.Glu902Gln (E902Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLD1 Glu902Gln was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. POLD1 Glu902Gln occurs at a position that is conserved across species and is not located in a known functional domain (Preston 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Multiple splicing models predict that this variant may destroy the natural splice donor site for intron 21 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether POLD1 Glu902Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Invitae | RCV001222421 | SCV001394519 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 902 of the POLD1 protein (p.Glu902Gln). This variant is present in population databases (rs373951714, gnomAD 0.02%). 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: 246161). 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. |