ENIGMA consortium uses RNA splicing data to reclassify BRCA1 exon 18 variants
The Evidence-based Network for the Interpretation of Germline Mutant Alleles tested 166 BRCA1 exon 18 variants using minigene assays. They analyzed blood RNA from 51 individuals and used mouse embryonic stem cells to evaluate repair capacity for 18 variants. Results from blood samples and minigene assays showed significant positive correlation. The mouse stem cell assays demonstrated that exon 18 skipping produces a protein that lacks rescue activity and cannot function. Linear regression analysis set classification thresholds at 59% or more full-length transcript levels and 30% functional transcripts, or less than 70% non-functional transcripts. Adding RNA splicing evidence shifted classifications: pathogenic calls rose from 28.6% to 31.7%, benign calls jumped from 3.7% to 24.4%, while uncertain classifications dropped from 18.9% to 8.5%. Experimental mRNA profiling changed interpretation for 34% of variants and resolved uncertainty in about 10% of cases. Exon 18 skipping proved less tolerated than other splicing events, suggesting the threshold for impaired BRCA1 function depends on which non-functional transcript results.
RNA-based evidence improved BRCA1 variant classification, cutting uncertain results nearly in half and providing clearer cancer risk information for genetic counseling.
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