Submissions for variant NM_007194.4(CHEK2):c.319+1G>T

dbSNP: rs765080766

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000792964	SCV000932295	likely pathogenic	Familial cancer of breast	2018-09-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the CHEK2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHEK2-related disease. Donor and acceptor splice site variants 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). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000997892	SCV001153650	likely pathogenic	not provided	2017-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002325499	SCV002609548	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	The c.319+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 1 of the CHEK2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, which is predicted to result in the in frame deletion of CDS1. As such, this alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitiation; however, direct evidence is insufficient at this time (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV000792964	SCV003806608	likely pathogenic	Familial cancer of breast	2023-01-17	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.