ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1489del (p.Asp497fs) (rs774175654)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164545 SCV000215201 pathogenic Hereditary cancer-predisposing syndrome 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Other strong data supporting pathogenic classification
GeneDx RCV000482135 SCV000564878 pathogenic not provided 2015-02-11 criteria provided, single submitter clinical testing This deletion of one nucleotide in CHEK2 is denoted c.1489delG at the cDNA level and p.Asp497IlefsX16 (D497IfsX16) at the protein level. The normal sequence, with the base that is deleted in brackets, is TCAA[G]ATCT. The deletion causes a frameshift, which changes an Aspartic Acid to an Isoleucine at codon 497, and creates a premature stop codon at position 16 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through protein truncation and is expected to remove the nuclear localization sequence (Roeb 2012). We therefore consider this variant to be pathogenic.
Invitae RCV000226984 SCV000289664 likely pathogenic Familial cancer of breast 2018-08-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CHEK2 gene (p.Asp497Ilefs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the CHEK2 protein The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 185176) This truncation is expected to remove the C-terminal nuclear localization signal (NLS) domain of the CHEK2 protein, which is necessary for it to carry-out its cellular functioning in the nucleus (PMID: 18004398). Experimental in vitro studies show that mutations in the C-terminal NLS domain result in the CHEK2 protein being predominantly localized in the cytoplasm (PMID: 12909615). In addition, phosphorylation of residue 516 located within the C-terminal NLS domain is required for optimal activation of CHEK2 and IR-induced apoptosis, and mutation of this residue results in a reduction of CHEK2 kinase activity and impairment of CHEK2-ionizing radiation-induced apoptosis (PMID: 12855706). Together, this data suggests that loss of the C-terminal NLS domain is detrimental for CHEK2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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