Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002473010 | SCV000544030 | uncertain significance | not provided | 2025-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1870 of the POLE protein (p.Arg1870His). This variant is present in population databases (rs758619238, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405714). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE 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 | RCV002348281 | SCV002648360 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-06 | criteria provided, single submitter | clinical testing | The p.R1870H variant (also known as c.5609G>A), located in coding exon 41 of the POLE gene, results from a G to A substitution at nucleotide position 5609. The arginine at codon 1870 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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. |
| Gene |
RCV002473010 | SCV002770121 | uncertain significance | not provided | 2024-07-07 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22722202, 29056344) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155186 | SCV003845081 | uncertain significance | not specified | 2023-02-03 | criteria provided, single submitter | clinical testing | Variant summary: POLE c.5609G>A (p.Arg1870His) results in a non-conservative amino acid change located in the DNA polymerase epsilon, catalytic subunit A, C-terminal domain (IPR013697) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251448 control chromosomes (gnomAD). 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.5609G>A in individuals affected with colorectal cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |