Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000657044 | SCV000289480 | uncertain significance | not provided | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2244 of the POLE protein (p.Leu2244Phe). This variant is present in population databases (rs375741031, 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: 240616). 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 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. |
Gene |
RCV000657044 | SCV000322141 | uncertain significance | not provided | 2023-08-30 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in both cases and controls in an ovarian cancer study (Song et al., 2021); This variant is associated with the following publications: (PMID: 23292937, 19296856, 32546565) |
Laboratory for Molecular Medicine, |
RCV000255330 | SCV000712557 | uncertain significance | not specified | 2016-11-15 | criteria provided, single submitter | clinical testing | The p.Leu2244Phe variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 11/66236 of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375741031). Computational prediction tools and conservation analysis sug gest that this variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In summary, the clinical signific ance of the p.Leu2244Phe variant is uncertain. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000657044 | SCV000888574 | uncertain significance | not provided | 2017-12-04 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV002479921 | SCV000894722 | uncertain significance | Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency | 2021-11-10 | criteria provided, single submitter | clinical testing | |
St. |
RCV000233704 | SCV002032286 | uncertain significance | Colorectal cancer, susceptibility to, 12 | 2021-11-11 | criteria provided, single submitter | clinical testing | The POLE c.6730C>T (p.Leu2244Phe) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133201508-G-A?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in in individuals with POLE-related disease, tumors exhibiting microsatellite instability (MSI-H), or tumors with a high mutational burden. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. |
Center for Genomic Medicine, |
RCV000255330 | SCV004027278 | uncertain significance | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Genome |
RCV000233704 | SCV004228780 | not provided | Colorectal cancer, susceptibility to, 12 | no assertion provided | phenotyping only | Variant interpreted as Uncertain significance and reported on 09-20-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. |