Submissions for variant NM_007194.4(CHEK2):c.1563del (p.Arg523fs)

dbSNP: rs786202339

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165099	SCV000215807	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The c.1563delG variant, located in coding exon 14 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1563, causing a translational frameshift with a predicted alternate stop codon (p.R523Vfs*43). This deletion and subsequent frameshift occurs near the 3' terminus of CHEK2 and results in the last 21 amino acids being replaced by alternate amino acid residues and the elongation of the encoded protein by 21 additional amino acids. The altered amino acids are not predicted to disrupt the nuclear localization signal of the protein (Zannini L et al. J Biol Chem, 2003 Oct;278:42346-51). However, the added amino acids do change the nature of the C-terminal protein from hydrophilic and disordered to hydrophobic (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000215708	SCV000279635	uncertain significance	not provided	2019-12-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation as the last 21 amino acids are lost and replaced with 42 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12909615, 18004398)
Invitae	RCV000234361	SCV000289669	uncertain significance	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the CHEK2 gene (p.Arg523Valfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 21 amino acid(s) of the CHEK2 protein and extend the protein by 21 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with ovarian cancer (PMID: 28888541). ClinVar contains an entry for this variant (Variation ID: 185645). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000234361	SCV003921100	uncertain significance	Familial cancer of breast	2023-02-10	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM4, PM2_SUP