Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000813820 | SCV000954197 | likely pathogenic | Familial cancer of breast | 2021-09-05 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 657247). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. |
| Ambry Genetics | RCV001024696 | SCV001186762 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-12-19 | criteria provided, single submitter | clinical testing | The c.593-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 4 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, these models predict a strong cryptic acceptor site leading to an in frame transcript with unknown functional impact that may lead to a clinically viable protein; direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV000813820 | SCV004217631 | uncertain significance | Familial cancer of breast | 2023-07-14 | criteria provided, single submitter | clinical testing |