Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002018750 | SCV002261322 | likely pathogenic | Familial cancer of breast | 2021-04-28 | criteria provided, single submitter | clinical testing | 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, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CHEK2-related conditions. This variant is not present in population databases (ExAC no frequency). This variant results in the deletion of part of exon 4 (c.445-8_446del) 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). |
MGZ Medical Genetics Center | RCV002018750 | SCV002579192 | likely pathogenic | Familial cancer of breast | 2022-05-20 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002331557 | SCV002634241 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-04 | criteria provided, single submitter | clinical testing | The c.445-8_446del10 variant results from a deletion of 10 nucleotides between positions c.445-8 and c.446 and involves the canonical splice acceptor site before coding exon 3 of the CHEK2 gene. The canonical splice acceptor site is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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. As such, this alteration is classified as likely pathogenic. |
Myriad Genetics, |
RCV002018750 | SCV004045395 | likely pathogenic | Familial cancer of breast | 2023-06-23 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |