Submissions for variant NM_007194.4(CHEK2):c.1510G>T (p.Glu504Ter)

dbSNP: rs587782489

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657698	SCV000779447	likely pathogenic	not provided	2019-09-30	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation: nonsense-mediated decay not predicted to occur, last 40 amino acids are lost, truncation disrupts the nuclear localization signal domain (Roeb 2012); Not observed at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 30413523, 29922827)
Invitae	RCV001377422	SCV001574753	likely pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu504*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the CHEK2 protein. This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with unspecified cancer (PMID: 32805687). ClinVar contains an entry for this variant (Variation ID: 545987). 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.
Ambry Genetics	RCV002388160	SCV002703629	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-03-22	criteria provided, single submitter	clinical testing	The p.E504* variant (also known as c.1510G>T), located in coding exon 13 of the CHEK2 gene, results from a G to T substitution at nucleotide position 1510. This changes the amino acid from a glutamic acid to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40 amino acids of the protein. However, 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV001377422	SCV004044310	pathogenic	Familial cancer of breast	2023-06-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV001377422	SCV004217730	likely pathogenic	Familial cancer of breast	2022-08-16	criteria provided, single submitter	clinical testing