Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000468962 | SCV000550442 | likely pathogenic | Familial cancer of breast | 2023-10-22 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 13 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: 410011). 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 skipping of exon 13 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. |
| Ambry Genetics | RCV000561946 | SCV000665166 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-03 | criteria provided, single submitter | clinical testing | The c.1461+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the CHEK2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000561946 | SCV001347278 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-01 | criteria provided, single submitter | clinical testing | This variant causes a G>A nucleotide substitution at the +5 position of intron 13 of the CHEK2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Institute of Human Genetics, |
RCV000468962 | SCV001428520 | uncertain significance | Familial cancer of breast | 2018-08-09 | criteria provided, single submitter | clinical testing | This variant was identified as de novo |
| MGZ Medical Genetics Center | RCV000468962 | SCV002581732 | uncertain significance | Familial cancer of breast | 2022-08-01 | criteria provided, single submitter | clinical testing | |
| Zotz- |
RCV003444238 | SCV004171684 | uncertain significance | Li-Fraumeni syndrome 2 | 2023-11-24 | no assertion criteria provided | clinical testing |