Submissions for variant NM_007194.4(CHEK2):c.908+1G>A

dbSNP: rs587781699

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129866	SCV000184683	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	The c.908+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the CHEK2 gene. This variant has been reported in three individuals undergoing multi-gene panel testing (Leedom TP et al. Cancer Genet, 2016 09;209:403-407). 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, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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.
Invitae	RCV000546023	SCV000633231	likely pathogenic	Familial cancer of breast	2023-09-25	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. Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 141374). Disruption of this splice site has been observed in individual(s) with prostate cancer (PMID: 31214711, 32832836). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Color Diagnostics, LLC DBA Color Health	RCV000129866	SCV001347410	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-09-22	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +1 position of intron 8 of the CHEK2 gene. 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 three individuals who underwent cancer genetic testing (PMID: 27751358). At least two other canonical splice site variants at the intron 8 splice donor site have been reported in individuals affected with breast cancer (PMID: 31742824 and http://www.aimjournal.ir/PDF/aim-23-155.pdf). 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.
GeneDx	RCV002225428	SCV002504443	likely pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; No data available from control populations to assess the frequency of this variant; Observed in individuals undergoing multi-gene panel testing for hereditary cancer risk (Leedom 2016); This variant is associated with the following publications: (PMID: 27751358, 28152038, 31214711)
Myriad Genetics, Inc.	RCV000546023	SCV004044443	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.