Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000470664 | SCV000564065 | likely pathogenic | Familial cancer of breast | 2016-11-10 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon 15 of the CHEK2 gene. The 5' boundary is likely confined to intron 14. 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. A gross deletion of exon 15 has not been reported in the literature in individuals with a CHEK2-related disease. This deletion removes amino acids 515-543 of the CHEK2 protein. Experimental studies have shown that amino acids 515-522 contain a nuclear localization signal, and that CHEK2 without 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 is a novel exon deletion that removes a portion of the CHEK2 protein that is required for its function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |