Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000476770 | SCV000564066 | pathogenic | Familial cancer of breast | 2016-12-20 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 3-4 of the CHEK2 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. Loss-of-function variants in CHEK2, including exon-level deletions, are known to be pathogenic. A deletion of exons 3-4 has been reported in the literature in an individual undergoing hereditary cancer testing (PMID: 24763289). This variant is expected to result in the in-frame deletion of 91 amino acids in the CHEK2 protein (Glu107-Lys197). While this is not anticipated to result in nonsense mediated decay, it will delete the entire forkhead-associated (FHA) domain (residues 115-175) of the CHEK2 protein (PMID: 18004398). The FHA domain has been shown to be important in mediating CHEK2 phosphorylation and dimerization, which are critical for normal CHEK2 functioning (PMID: 11390408, 11053450, 12024051, 18004398). For these reasons, this variant has been classified as Pathogenic. |