Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium

Mara Colombo, Marinus J. Blok, Phillip Whiley, Marta Santamarina, Sara Gutierrez-Enriquez, Atocha Romero, Pilar Garre, Alexandra Becker, Lindsay Denise Smith, Giovanna De Vecchi, Rita D. Brandao, Demis Tserpelis, Melissa Brown, Ana Blanco, Sandra Bonache, Mireia Menendez, Claude Houdayer, Claudia Foglia, James D. Fackenthal, Diana BaralleBarbara Wappenschmidt, Eduardo Diaz-Rubio, Trinidad Caldes, Logan Walker, Orland Diez, Ana Vega, Amanda B. Spurdle, Paolo Radice, Miguel De La Hoya*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

62 Citations (Web of Science)


Loss-of-function germline mutations in BRCA1 (MIM #113705) confer markedly increased risk of breast and ovarian cancer. The full-length transcript codifies for a protein involved in DNA repair pathways and cell-cycle checkpoints. Several BRCA1 splicing isoforms have been described in public domain databases, but the physiological role (if any) of BRCA1 alternative splicing remains to be established. An accurate description of 'naturally occurring' alternative splicing at this locus is a prerequisite to understand its biological significance. However, a systematic analysis of alternative splicing at the BRCA1 locus is yet to be conducted. Here, the Evidence-Based Network for the Interpretation of Germ-Line Mutant Alleles consortium combines RT-PCR, exon scanning, cloning, sequencing and relative semi-quantification to describe naturally occurring BRCA1 alternative splicing with unprecedented resolution. The study has been conducted in blood-related RNA sources, commonly used for clinical splicing assays, as well as in one healthy breast tissue. We have characterized a total of 63 BRCA1 alternative splicing events, including 35 novel findings. A minimum of 10 splicing events (Delta 1Aq, Delta 5, Delta 5q, Delta 8p, Delta 9, Delta(9,10), Delta 9_11, Delta 11q, Delta 13p and Delta 14p) represent a substantial fraction of the full-length expression level (ranging from 5 to 100%). Remarkably, our data indicate that BRCA1 alternative splicing is similar in blood and breast, a finding supporting the clinical relevance of blood-based in vitro splicing assays. Overall, our data suggest an alternative splicing model in which most non-mutually exclusive alternative splicing events are randomly combined into individual mRNA molecules to produce hundreds of different BRCA1 isoforms.
Original languageEnglish
Pages (from-to)3666-3680
JournalHuman Molecular Genetics
Issue number14
Publication statusPublished - 15 Jul 2014

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