Submissions for variant NM_007194.4(CHEK2):c.1502_1503dup (p.Glu502fs)

dbSNP: rs587782707

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132173	SCV000187252	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The c.1502_1503dupAG pathogenic mutation, located in coding exon 13 of the CHEK2 gene, results from a duplication of AG at nucleotide position 1502, causing a translational frameshift with a predicted alternate stop codon (p.E502Rfs*12). This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 7.7% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration was identified amongst multiple cohorts of African American prostate and breast cancer patients (Ademuyiwa FO et al. Breast Cancer Res Treat, 2019 Nov;178:151-159; Palmer JR et al. J Natl Cancer Inst, 2020 Dec;112:1213-1221; Trendowski MR et al. JCO Precis Oncol, 2022 Nov;6:e2200460). 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	RCV000132173	SCV000684605	pathogenic	Hereditary cancer-predisposing syndrome	2015-10-06	criteria provided, single submitter	clinical testing
Invitae	RCV001064635	SCV001229545	likely pathogenic	Familial cancer of breast	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu502Argfs*12) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the CHEK2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32427313). ClinVar contains an entry for this variant (Variation ID: 142772). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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.
Myriad Genetics, Inc.	RCV001064635	SCV004044234	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.
Baylor Genetics	RCV001064635	SCV004217751	likely pathogenic	Familial cancer of breast	2021-10-28	criteria provided, single submitter	clinical testing