Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000164545 | SCV000215201 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-06 | criteria provided, single submitter | clinical testing | The c.1489delG pathogenic mutation, located in coding exon 13 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.D497Ifs*16). This alteration occurs at the 3' terminus of the CHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 47 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV000226984 | SCV000289664 | likely pathogenic | Familial cancer of breast | 2023-07-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Asp497Ilefs*16) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acid(s) of the CHEK2 protein. This variant is present in population databases (rs774175654, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 185176). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Gene |
RCV000482135 | SCV000564878 | likely pathogenic | not provided | 2023-05-02 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation, as the last 47 amino acids are replaced with 15 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with prostate cancer (Matejcic et al., 2020); This variant is associated with the following publications: (PMID: 32832836, 32805687, 29922827, 19782031, 22419737) |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000482135 | SCV001134157 | pathogenic | not provided | 2018-10-09 | criteria provided, single submitter | clinical testing | The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. |
Myriad Genetics, |
RCV000226984 | SCV004043289 | pathogenic | Familial cancer of breast | 2023-06-29 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
Baylor Genetics | RCV000226984 | SCV004217753 | likely pathogenic | Familial cancer of breast | 2021-10-17 | criteria provided, single submitter | clinical testing | |
BRCAlab, |
RCV000226984 | SCV002588976 | pathogenic | Familial cancer of breast | 2022-08-26 | no assertion criteria provided | clinical testing |