Submissions for variant NM_007194.3(CHEK2):c.1462-?_1542+?del

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000240587	SCV000299132	uncertain significance	Familial cancer of breast	2016-11-03	criteria provided, single submitter	clinical testing	This variant is a gross deletion of the genomic region encompassing exon 14 of the CHEK2 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. While deletions encompassing exon 14 have not been reported in the literature, loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This exact variant has been observed in several individuals affected with breast cancer (Invitae database). However, there is insufficient evidence to conclude whether this variant segregates with disease or not. This variant is expected to result in an in-frame, truncated CHEK2 protein lacking amino acids Asp488-Gln514. This deleted region lies adjacent to the Ser516 phosphorylation site, as well as the nuclear localization signal (residues 515-522), both necessary for normal CHEK2 functioning (PMID: 12855706, 18538787, 12909615, 18004398). However, it is uncertain whether this deletion impacts these critical CHEK2 protein domains. In summary, this is a rare in-frame deletion with uncertain impact on protein function. Without additional functional and/or genetic data, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589230	SCV000698782	uncertain significance	not provided	2016-03-31	criteria provided, single submitter	clinical testing	Variant summary: This variant identified by an alternate technology (non-sequencing) involves the deletion of exon 14 in the CHEK2 gene. A presumed nomenclature of c.1462_1542del has been designated for the purposes of this classification. Exon 14 is the second to last exon in the gene and encodes part of the protein kinase-like domain. HGMD cites only two truncating mutations located in exon 14 or 15, and considering the location of this deletion, the effect on the protein structure is unclear at this time. The variants presence in the general population cannot be assessed by ExAC, ESP or 1000G as these databases use sequencing technology that cannot detect deletions this large. There has been one report of the variant from a thesis in which an Non-Hodgkin Lymphoma patient was found to have the deletion via MLPA, however no copy number variants were detected in this region by array comparative genomic hybridisation (aCGH), thus the true presence of this variant in the patient was not confirmed. Additionally, CHEK2 exons 10-14 are wholly or partially duplicated as pseudogenes eight times in the human genome, with duplications retaining the CHEK2 intron structure (PMID: 15649950), thus it is difficult to identify if the exon 14 deletion is the CHEK2 gene or its pseudogenes. Considering the lack of reported patients carrying this variant, the lack of functional studies, and the presence of this variant toward the end of the gene, this variant has been classified as a VUS until additional evidence becomes available.