BRCA1 and BRCA2 5 ' noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

Leslie J. Burke*, Jan Sevcik, Gaetana Gambino, Emma Tudini, Eliseos J. Mucaki, Ben C. Shirley, Phillip Whiley, Michael T. Parsons, Kim De Leeneer, Sara Gutierrez-Enriquez, Marta Santamarina, Sandrine M. Caputo, Elizabeth Santana dos Santos, Jana Soukupova, Marketa Janatova, Petra Zemankova, Klara Lhotova, Lenka Stolarova, Mariana Borecka, Alejandro Moles-FernandezSiranoush Manoukian, Bernardo Bonanni, Stacey L. Edwards, Marinus J. Blok, Thomas van Overeem Hansen, Maria Rossing, Orland Diez, Ana Vega, Kathleen B. M. Claes, David E. Goldgar, Etienne Rouleau, Paolo Radice, Paolo Peterlongo, Peter K. Rogan, Maria Caligo, Amanda B. Spurdle, Melissa A. Brown, ENIGMA Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5 ' noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.
Original languageEnglish
Pages (from-to)2025-2039
Number of pages15
JournalHuman Mutation
Issue number12
Publication statusPublished - 1 Dec 2018


  • breast cancer
  • BRCA1
  • BRCA2
  • promoter
  • transcription
  • variants of unknown clinical significance (VUS)
  • RISK


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