Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001026958 | SCV001189439 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-02-02 | criteria provided, single submitter | clinical testing | The c.792+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 5 in the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV001026958 | SCV001350632 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-02-12 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001862391 | SCV002168405 | likely pathogenic | Familial cancer of breast | 2023-07-10 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 6 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 not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 827336). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. |