Submissions for variant NM_007194.4(CHEK2):c.593-1G>A

dbSNP: rs786203229

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166451	SCV000217247	likely pathogenic	Hereditary cancer-predisposing syndrome	2014-10-29	criteria provided, single submitter	clinical testing	The c.593-1G>A intronic variant, results from a G to A one nucleotide upstream from coding exon 4 of the CHEK2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6448 samples (12896 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.004% (greater than 26000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the acceptor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.593-1G>A variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850343	SCV002276834	likely pathogenic	Familial cancer of breast	2021-12-24	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the CHEK2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer, colorectal cancer, kidney cancer, and/or prostate cancer (PMID: 25186627, 29659569, 32906215). ClinVar contains an entry for this variant (Variation ID: 186800). 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 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.	RCV001850343	SCV004044250	likely pathogenic	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV001850343	SCV004217765	likely pathogenic	Familial cancer of breast	2021-03-26	criteria provided, single submitter	clinical testing