Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000806398 | SCV000946394 | likely pathogenic | Familial cancer of breast | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change affects a donor 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 (gnomAD no frequency). 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: 651111). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
Ambry Genetics | RCV002352383 | SCV002650387 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-16 | criteria provided, single submitter | clinical testing | The c.592+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration at this same donor site, CHEK2 c.592+3A>T, 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. Based on the majority of available evidence to date, this alteration is classified as a disease-causing mutation. |
Myriad Genetics, |
RCV000806398 | SCV004043399 | likely pathogenic | Familial cancer of breast | 2023-06-26 | 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. |