Submissions for variant NM_007194.4(CHEK2):c.1462-1G>A

gnomAD frequency: 0.00001  dbSNP: rs1060502698

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474737	SCV000550477	pathogenic	Familial cancer of breast	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 13 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. 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 (PMID: 32427313). ClinVar contains an entry for this variant (Variation ID: 410026). Studies have shown that disruption of this splice site results in activation of cryptic splice sites, and produces a non-functional protein and/or introduces a premature termination codon (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000773145	SCV000906666	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -1 position of intron 13 of the CHEK2 gene. This variant is also known as c.1591-1G>A based on the reference transcript NM_001005735.1 in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 32427313, Color internal data), and individuals affected with pancreatic and ovarian cancer (PMID: 28888541, 29731985). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000773145	SCV001172048	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	The c.1462-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 13 of the CHEK2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. This alteration has been reported in the literature in an individual with breast cancer (Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Although the resulting aberrant transcripts are not expected to trigger nonsense-mediated decay, they are located in a critical region of the protein (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. 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.	RCV000474737	SCV004043341	likely pathogenic	Familial cancer of breast	2023-06-29	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.