Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000555929 | SCV000632914 | likely pathogenic | Familial cancer of breast | 2018-03-08 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 14-15 of the CHEK2 gene. The 5' boundary is likely confined to intron 13. 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 CHEK2 protein. This variant has not been reported in the literature in individuals with a CHEK2-related disease, but has been identified by Invitae in an individual affected with breast cancer. This deletion removes amino acids 488-543 of the CHEK2 protein. Experimental studies have shown that amino acids 515-522 contain a nuclear localization signal, and that CHEK2, when lacking these residues, localizes to the cytoplasm instead of the nucleus. In addition, phosphorylation of the serine residue at codon 516 is required for normal CHEK2 function (PMID: 12909615, 12855706, 18004398). In summary, this variant removes a portion of the CHEK2 protein that is required for its function. For these reasons, this variant has been classified as Likely Pathogenic. |