Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000635635 | SCV000757056 | pathogenic | Familial cancer of breast | 2023-10-28 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 7 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). Disruption of this splice site has been observed in individual(s) with colorectal cancer and breast cancer (PMID: 28944238; Invitae). This variant is also known as c.975+1G>T. ClinVar contains an entry for this variant (Variation ID: 530044). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002448967 | SCV002676681 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-10 | criteria provided, single submitter | clinical testing | The c.846+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. This variant was reported in 3/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV000635635 | SCV004044192 | likely pathogenic | Familial cancer of breast | 2023-06-27 | 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. |
| Baylor Genetics | RCV000635635 | SCV004217721 | pathogenic | Familial cancer of breast | 2022-11-06 | criteria provided, single submitter | clinical testing |