Submissions for variant NM_007194.4(CHEK2):c.684-2A>G

dbSNP: rs2053419665

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001377776	SCV001575199	likely pathogenic	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 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). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 1066705). 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.
Genetics and Molecular Pathology, SA Pathology	RCV001377776	SCV002556725	pathogenic	Familial cancer of breast	2022-04-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002368214	SCV002665000	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-01-28	criteria provided, single submitter	clinical testing	The c.684-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been identified in a cohort of families with multiple breast and/or ovarian cancer diagnoses undergoing multigene panel testing (Li J et al. J. Med. Genet. 2016 Jan;53:34-42). This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and none of 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this alteration is also designated as c.813-2A>G in the published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Fulgent Genetics, Fulgent Genetics	RCV002499777	SCV002810263	likely pathogenic	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-05-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001377776	SCV004045701	likely pathogenic	Familial cancer of breast	2023-06-26	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.
Color Diagnostics, LLC DBA Color Health	RCV002368214	SCV004361383	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 5 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast cancer (PMID: 26534844, 29522266, 30287823). 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.