Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000226329 | SCV000289837 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2020-09-18 | criteria provided, single submitter | clinical testing | 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. This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Ser217Valfs*17). It is expected to result in an absent or disrupted protein product. However, this sequence variant may be functionally rescued by a naturally occurring isoform of BRCA1 lacking exons 8 and 9. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 240828). Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, detailed characterization of the splicing patterns of the BRCA1 gene has identified an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10). This Δ8-9 isoform is highly expressed in normal breast tissue and blood of unaffected individuals, suggesting it may not be deleterious. In addition, this naturally occurring isoform results in the in-frame deletion of 41 amino acid residues that do not overlap a known clinically important functional domain of the BRCA1 protein, and therefore may retain functional activity (PMID: 24569164, 30832263). Taken together, these observations suggest that the Δ8-9 isoform has the potential to maintain BRCA1 protein function and rescue loss-of-function variants within these exons (PMID: 24569164, 27008870). Additional clinical and/or functional data is required to establish the pathogenicity of these variants. |