Submissions for variant NM_007194.4(CHEK2):c.847-1G>A

dbSNP: rs878854926

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227592	SCV000289710	likely pathogenic	Familial cancer of breast	2022-09-29	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: 240758). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 32427313). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 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	RCV002444910	SCV002676707	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-11-09	criteria provided, single submitter	clinical testing	The c.847-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 7 of the CHEK2 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV000227592	SCV004045135	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.
Color Diagnostics, LLC DBA Color Health	RCV002444910	SCV004361372	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the canonical -1 position of intron 7 splice acceptor site of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional RNA studies have not been reported for this variant, it is expected to disrupt CHEK2 protein function. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant impacting a canonical position c.847-2A>G in intron 7 splice acceptor site is reported to be disease-causing (ClinVar variation ID: 822474). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001579299	SCV001805833	pathogenic	Breast carcinoma	2021-08-21	no assertion criteria provided	clinical testing	Invasive Breast Carcinoma EST= + PRO = + HER2 = + KI = 30%