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

L.J. Burke, J. Sevcik, G. Gambino, E. Tudini, E.J. Mucaki, B.C. Shirley, P. Whiley, M.T. Parsons, K. De Leeneer, S. Gutiérrez-Enríquez, M. Santamariña, S.M. Caputo, E. Santana dos Santos, J. Soukupova, M. Janatova, P. Zemankova, K. Lhotova, L. Stolarova, M. Borecka, A. Moles-FernándezS. Manoukian, B. Bonanni, S.L. Edwards, M.J. Blok, T. van Overeem Hansen, M. Rossing, O. Diez, A. Vega, K.B.M. Claes, D.E. Goldgar, E. Rouleau, P. Radice, P. Peterlongo, P.K. Rogan, M. Caligo, A.B. Spurdle, M.A. Brown, ENIGMA Consortium

Research output: Contribution to journalArticlepeer-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 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. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)2025-2039
Number of pages15
JournalHuman Mutation
Issue number12
Publication statusPublished - 2018


  • BRCA1
  • BRCA2
  • breast cancer
  • promoter
  • transcription
  • variants of unknown clinical significance (VUS)
  • BRCA1 protein
  • BRCA2 protein
  • transcription factor PAX5
  • adult
  • Article
  • bioinformatics
  • cancer patient
  • clinical classification
  • controlled study
  • female
  • gel mobility shift assay
  • gene frequency
  • genetic variability
  • human
  • luciferase assay
  • major clinical study
  • middle aged
  • next generation sequencing
  • priority journal
  • promoter region
  • protein binding
  • transcription regulation
  • tumor suppressor gene

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