Submissions for variant NM_007194.4(CHEK2):c.1461+1G>A

dbSNP: rs886039629

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255259	SCV000322553	likely pathogenic	not provided	2021-12-17	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek 2016); Identified in a cohort of predominantly healthy individuals undergoing clinical genetic testing (The eMERGE Consortium 2019); This variant is associated with the following publications: (PMID: 25839328, 31447099)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468702	SCV000550445	likely pathogenic	Familial cancer of breast	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 13 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). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 265565). 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.
Ambry Genetics	RCV000569979	SCV000669232	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The c.1461+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 12 of the CHEK2 gene. 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. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, however, direct evidence is insufficient at this time (Ambry internal data). 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000468702	SCV000839937	pathogenic	Familial cancer of breast	2017-03-07	criteria provided, single submitter	clinical testing	This c.1461+1G>A variant has not been observed in our cohort database nor has been detected in the ExAC database. This variant was however reported in ClinVar but the clinical presentation of the patient was not available (SCV000322553.3). This variant affects the invariant donor splice site of intron 13 of the CHEK2 gene. Whole not validated for clinical use, computer-based algorithms predict this c.1461+1G>A change to disrupt this splicing site. A c.1461 +2T>C affecting the same invariant splice site was reported in a cohort of patients with breast and/or ovarian cancer [PMID 24549055]. This variant is classified as pathogenic.
MGZ Medical Genetics Center	RCV000468702	SCV002579863	likely pathogenic	Familial cancer of breast	2022-02-14	criteria provided, single submitter	clinical testing