Submissions for variant NM_007194.4(CHEK2):c.1528C>T (p.Gln510Ter)

dbSNP: rs886039512

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254950	SCV000322206	likely pathogenic	not provided	2016-07-27	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1528C>T at the cDNA level and p.Gln510Ter (Q510X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG). Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 34 amino acids are no longer translated correctly and is predicted to cause loss of normal protein function through protein truncation. Furthermore, this variant disrupts the nuclear localization signal (Roeb 2012). This variant has been reported in at least one individual diagnosed with breast cancer under the age of 45 (Le Calvez-Kelm 2011), and is considered likely pathogenic.
Ambry Genetics	RCV001012022	SCV001172421	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-13	criteria provided, single submitter	clinical testing	The p.Q510* pathogenic mutation (also known as c.1528C>T), located in coding exon 13 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1528. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of CHEK2, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 34 amino acids of the protein. However, premature stop codons are typically deleterious in nature and this mutation 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 mutation has been reported in 1/1313 early onset (less than 45 years) breast cancer cases and 0/1123 controls (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6) and also in a cohort of BRCA1/2-negative familial breast cancer cases (Li J et al. J. Med. Genet. 2016 Jan;53(1):34-42). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001046816	SCV001210733	likely pathogenic	Familial cancer of breast	2022-08-28	criteria provided, single submitter	clinical testing	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: 21244692, 26534844). ClinVar contains an entry for this variant (Variation ID: 265377). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This sequence change creates a premature translational stop signal (p.Gln510*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the CHEK2 protein.
Myriad Genetics, Inc.	RCV001046816	SCV004043326	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.