Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000518951 | SCV000617796 | pathogenic | not provided | 2015-11-19 | criteria provided, single submitter | clinical testing | The c.2308-2A>G pathogenic variant in the BLM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2308-2A>G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2308-2A>G as a pathogenic variant |
Ambry Genetics | RCV001015149 | SCV001175954 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-11-21 | criteria provided, single submitter | clinical testing | The c.2308-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 10 in the BLM gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. |
Invitae | RCV002525121 | SCV003482351 | likely pathogenic | Bloom syndrome | 2022-03-24 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 10 of the BLM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BLM are known to be pathogenic (PMID: 17407155). This variant has not been reported in the literature in individuals affected with BLM-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 449542). |