ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1260-8A>G

gnomAD frequency: 0.00001  dbSNP: rs863224747
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196032 SCV000254921 uncertain significance Familial cancer of breast 2024-01-24 criteria provided, single submitter clinical testing This sequence change falls in intron 11 of the CHEK2 gene. It does not directly change the encoded amino acid sequence of the CHEK2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 31050813). ClinVar contains an entry for this variant (Variation ID: 216641). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 31050813; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000481621 SCV000567855 likely pathogenic not provided 2019-10-22 criteria provided, single submitter clinical testing Non-canonical splice site variant demonstrated to result in loss-of-function (Kleiblova 2019); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31050813, 23054060)
Color Diagnostics, LLC DBA Color Health RCV000582062 SCV000689646 likely pathogenic Hereditary cancer-predisposing syndrome 2023-01-26 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -8 position of intron 11 of the CHEK2 gene. RNA studies with multiple carrier individuals have shown that this variant creates a new splice acceptor site that results in the inclusion of 7 intronic nucleotides and, subsequently, frameshift and premature protein translation start signal (PMID: 31050813; ClinVar SCV002681983.1). This variant has been reported in an individual affected with familial breast cancer (PMID: 31050813) and in several unaffected individuals (PMID: 31050813). 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.
Counsyl RCV000196032 SCV000785488 uncertain significance Familial cancer of breast 2017-08-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000582062 SCV002681983 pathogenic Hereditary cancer-predisposing syndrome 2023-07-25 criteria provided, single submitter clinical testing The c.1260-8A>G intronic pathogenic mutation results from an A to G substitution 8 nucleotides upstream from coding exon 11 in the CHEK2 gene. This nucleotide position is well conserved in available vertebrate species. 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 that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics RCV000196032 SCV004217674 likely pathogenic Familial cancer of breast 2023-05-25 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV003483572 SCV004228263 likely pathogenic Hereditary breast ovarian cancer syndrome 2023-10-08 criteria provided, single submitter curation Splice Prediction positive, Splice effect experimentally proven by Kleiblova et al. 2019. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Splice effect experimentally proven by Kleiblova et al. 2019 and Ambry Genetics, PM2 (supporting pathogenic): Absent from gnomAD, PP3 (supporting pathogenic): SpliceAI Score 0.99
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000481621 SCV002036828 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000481621 SCV002037439 uncertain significance not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.