Submissions for variant NM_007194.4(CHEK2):c.1096-1G>A

dbSNP: rs1060502716

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000464247	SCV000550542	likely pathogenic	Familial cancer of breast	2022-12-30	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 410056). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 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).
Ambry Genetics	RCV000565790	SCV000666349	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-30	criteria provided, single submitter	clinical testing	The c.1096-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 10 of the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Ambry Genetics	RCV000624531	SCV000741408	likely pathogenic	Inborn genetic diseases	2016-03-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001782952	SCV002019283	pathogenic	not provided	2019-05-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000464247	SCV004043366	likely pathogenic	Familial cancer of breast	2023-06-27	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.