Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000819221 | SCV000959868 | pathogenic | Familial cancer of breast | 2018-11-21 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 10-15 of the CHEK2 gene. The 5' boundary is likely confined to intron 9. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. While this gross deletion has not been reported in the literature, loss-of-function variants including gross deletions in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This deletion (p.Tyr337_Leu543del) partially removes the kinase domain (residues 226-486), and the NLS (nuclear localization signal, residues 515-522), which are important for normal CHEK2 protein function (PMID: 11733767, 15279791, 19782031, 12909615, 18004398, 24879340). Smaller in-frame deletions and truncations in this region have been determined to be pathogenic in the Invitae database, suggesting that deletion of this region of the CHEK2 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |