ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1501del (p.Glu501fs) (rs1131691045)

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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 RCV000492481 SCV000581178 pathogenic Hereditary cancer-predisposing syndrome 2016-06-06 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)
Color RCV000492481 SCV000684604 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Invitae RCV000635920 SCV000757347 likely pathogenic Familial cancer of breast 2017-10-27 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the CHEK2 gene (p.Glu501Argfs*12). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acids of the CHEK2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 428912). The last exon of the CHEK2 gene contains a nuclear localization signal (NLS), which is necessary for CHEK2 function in the nucleus (PMID: 12909615, 18004398, 24879340), as variants within the NLS result in the CHEK2 protein being mislocalized to the cytoplasm (PMID: 12909615). This frameshift is expected to remove the NLS domain. Also, other loss-of-function variants downstream of this codon (p.Ser516Leufs*50 and p.Arg519*) have been determined to be pathogenic (PMID: 12909615, 12855706). This suggests that this region is critical for CHEK2 protein function, and that loss-of-function variants upstream of those positions may also be pathogenic. 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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