RNA Splicing Tests Sharpen BRCA1 Variant Classification in 166-Variant Study
The ENIGMA consortium tested 166 BRCA1 exon 18 variants using minigene assays, blood RNA from 51 people, and mouse embryonic stem cell functional tests. Adding RNA splicing evidence raised pathogenic classifications from 28.6% to 31.7% and benign calls from 3.7% to 24.4%. Uncertain classifications dropped from 18.9% to 8.5%. The team found that exon 18 skipping produces a non-functional protein and that at least 59% full-length transcript or 30% functional transcript is needed for normal BRCA1 activity. Experimental RNA profiling changed the interpretation of 34% of variants and resolved uncertainty in about 10% of cases. Blood and minigene assays showed strong correlation, and mouse stem cell results were highly concordant.
More precise variant classification helps doctors and families make better decisions about hereditary breast cancer risk.
Written by the Genomes desk from the primary source linked above and checked against it. Research use only; not medical advice. Corrections: [email protected].