Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV000583186 | SCV000689727 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-09-24 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the -2 position of intron 6 of the CHEK2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. However, two different variants impacting a canonical -1 position at this splice site have been reported as disease-causing in ClinVar (variation ID: 182430, 801161), and one of which has been reported in individuals affected with breast and prostate cancer and shown to impact splicing in carrier RNA (PMID: 26681312, 29520813, 31349801). 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. |
Invitae | RCV001209317 | SCV001380746 | pathogenic | Familial cancer of breast | 2022-11-15 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 31349801; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 491642). Disruption of this splice site has been observed in individual(s) with breast cancer and prostate cancer (PMID: 26681312, 27751358, 29520813, 31349801; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the CHEK2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. |
Myriad Genetics, |
RCV001209317 | SCV004044942 | likely pathogenic | Familial cancer of breast | 2023-06-27 | 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. |