Submissions for variant NM_007194.4(CHEK2):c.1582G>T (p.Glu528Ter)

dbSNP: rs138040612

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590066	SCV000698788	uncertain significance	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.1582G>T (p.Glu528X) variant results in a premature termination codon, which is predicted to shorten the protein by 15 amino acids, which was indicated by InterPro to not harbor a known functional domain. The variant of interest was not observed in controls (ExAC), nor has it been, to our knowledge, reported in affected individuals via publications and/or databases/clinical diagnostic laboratories. To date, LCA has not classified any truncation variants downstream of this variant. In addition, ClinVar reports a downstream nonsense variant, c.1591G>T (p.Glu531X) as "uncertain significance." Therefore, due to the uncertainity of this variant being located relatively close to the termination stop codon, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until addtional information becomes available (ie, clinical and functional studies).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860143	SCV002279922	uncertain significance	Familial cancer of breast	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu528*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the CHEK2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 496344). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Ambry Genetics	RCV002404595	SCV002705622	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-28	criteria provided, single submitter	clinical testing	The p.E528* variant (also known as c.1582G>T), located in coding exon 14 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1582. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 16 amino acids of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000590066	SCV004034603	uncertain significance	not provided	2023-03-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 16 amino acids are lost; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge