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

dbSNP: rs1131691045

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492481	SCV000581178	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-18	criteria provided, single submitter	clinical testing	The c.1501delG pathogenic mutation, located in coding exon 13 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1501, causing a translational frameshift with a predicted alternate stop codon. This alteration occurs at the 3' terminus of the CHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 43 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration results in the truncation of the critical NLS-3 (nuclear localization signal-3) domain of the CHEK2 gene, which mediates proper localization of the protein (Zannini L et al. J. Biol. Chem. 2003 Oct; 278(43):42346-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000492481	SCV000684604	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-02-28	criteria provided, single submitter	clinical testing
Invitae	RCV000635920	SCV000757347	likely pathogenic	Familial cancer of breast	2021-08-19	criteria provided, single submitter	clinical testing	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. 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.
Myriad Genetics, Inc.	RCV000635920	SCV004045081	pathogenic	Familial cancer of breast	2023-06-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.