Submissions for variant NM_007194.4(CHEK2):c.793-1G>A

dbSNP: rs730881687

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160429	SCV000210975	likely pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in aberrant splicing, leading to protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Agiannitopoulos et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, prostate, and other cancers (Leedom et al., 2016; Schrader et al., 2016; Lilyquist et al., 2017; Wu et al., 2018, Agiannitopoulos et al., 2019; Germani et al., 2020); This variant is associated with the following publications: (PMID: 31589614, 32805687, 27751358, 26681312, 26556299, 24713400, 21876083, 25980754, 29520813, 31447099, 22419737, 19782031, 36425062, 35261632, 27009842, 31349801, 31970404, 28888541, 32957588)
Ambry Genetics	RCV000214915	SCV000273338	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The c.793-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the CHEK2 gene. One study identified this alteration in 1/703 patients with lethal prostate cancer and 0/1455 patients with localized prostate cancer (Wu Y et al. Prostate, 2018 Jun;78:607-615). This alteration has also been detected in multiple individuals undergoing multi-gene panel testing (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Leedom TP et al. Cancer Genet. 2016 Sep;209:403-407). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Agiannitopoulos K et al. BMC Med. Genet., 2019 07;20:131). 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. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000214915	SCV000537628	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the -1 position of intron 6 of the CHEK2 gene. Splice site prediction tools suggest that this variant may abolish the canonical splice acceptor site and create a new splice acceptor one basepair downstream. RNA studies have confirmed this prediction, with the variant resulting in the deletion of one nucleotide from the mRNA and a frameshift and premature termination codon within exon 7 of the protein (p.Asp265Thrfs*10) (PMID: 31349801, 37725924). This variant has been reported in individuals affected with breast cancer (PMID: 26556299, 26681312, 27751358, 31349801, 36529819) and prostate cancer (PMID: 29520813) in the literature. This variant has been reported in a homozygous individual with a personal and family history of cancer and multiple cytogenetic anomalies (PMID: 36529819). This variant has been identified in 4/249694 chromosomes 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.
Invitae	RCV000464029	SCV000550453	pathogenic	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 6 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. This variant is present in population databases (rs730881687, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast cancer and prostate cancer (PMID: 26681312, 27751358, 29520813, 31349801; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182430). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 31349801; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000464029	SCV000785943	likely pathogenic	Familial cancer of breast	2018-01-17	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000464029	SCV000839943	pathogenic	Familial cancer of breast	2017-06-02	criteria provided, single submitter	clinical testing	This c.793-1G>A variant in the CHEK2 gene 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 patients was not available (SCV000210975.9, SCV000273338.2). This variant affect the invariant acceptor splice site of intron 6 of the CHEK2 gene. While not clinically validated, computer-based algorithms predict this c.793-1G>A change to affect splicing by creating an alternative splice site 1bp downstream and thus creating a frameshift. This variant is classified as pathogenic.
GeneKor MSA	RCV000214915	SCV000890134	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-14	criteria provided, single submitter	clinical testing	This sequence change occurs 1 base before exon 7 of the CHEK2 gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. 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; PMID: 24713400). This mutation has been reported in individuals who underwent genetic testing for the risk of hereditary cancer, including breast cancer (PMID: 27751358). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this change disrupts the wild type acceptor site and activates an intronic cryptic splice acceptor 1 bp downstream, thus creating a frameshift. Experimental analysis in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing showed that this variant affects splicing by creating an alternative splice site 1 bp downstream which results in a frameshift effect and the generation of a premature translation stop signal 10 amino acid residues later, and is predicted to result in a truncated protein. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498796	SCV002809367	likely pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2021-07-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000464029	SCV004020113	likely pathogenic	Familial cancer of breast	2023-03-08	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.
Baylor Genetics	RCV000464029	SCV004217509	pathogenic	Familial cancer of breast	2023-10-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160429	SCV004221756	pathogenic	not provided	2022-02-14	criteria provided, single submitter	clinical testing	This variant disrupts a canonical splice-acceptor site and interferes with normal CHEK2 mRNA splicing. The frequency of this variant in the general population, 0.00012 (4/34412 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)), prostate cancer (PMID: 29520813 (2018)), and neuroblastoma (PMID: 27009842 (2016)), as well as an individual who underwent genetic testing for hereditary cancer risk (PMID: 31349801 (2019)). Based on the available information, this variant is classified as pathogenic.