Total submissions: 9
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. |
Gene |
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, |
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, |
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, |
RCV000481621 | SCV002036828 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000481621 | SCV002037439 | uncertain significance | not provided | no assertion criteria provided | clinical testing |