Identification of fifteen novel germline variants in the BRCA1 3′UTR reveals a variant in a breast cancer case that introduces a functional miR-103 target site

Brooke L. Brewster, Francesca Rossiello, Juliet D. French, Stacey L. Edwards, Ming Wong, Ania Wronski, Phillip Whiley, Nic Waddell, Xiaowei Chen, Betsy Bove, KconFab, John L. Hopper, Esther M. John, Irene Andrulis, Mary Daly, Sara Volorio, Loris Bernard, Bernard Peissel, Siranoush Manoukian, Monica BarileSara Pizzamiglio, Paolo Verderio, Amanda B. Spurdle, Paolo Radice, Andrew K. Godwin, Melissa C. Southey, Melissa A. Brown, Paolo Peterlongo

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38 Citations (Scopus)


Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in noncoding and untranslated regions (UTR). As 3′UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3′UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases, and controls. Fifteen novel BRCA1 3′UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.*528G>C, c.*718A>G, and c.*1271T>C and four found in controls, c.*309T>C, c.*379G>A, c.*823C>T, and c.*264C>T, reduced 3′UTR activity (P < 0.02), whereas two variants found in cases, c.*291C>T and c.*1139G>T, increased 3′UTR activity (P < 0.01). Three case variants, c.*718A>G, c.*800T>C, and c.*1340_1342delTGT, were predicted to create new miRNA binding sites and c.*1340_1342delTGT caused a reduction (25%, P = 0.0007) in 3′UTR reporter activity when coexpressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3′UTR variants published to date.

Original languageEnglish
Pages (from-to)1665-1675
Number of pages11
JournalHuman Mutation
Issue number12
Publication statusPublished - 1 Dec 2012
Externally publishedYes


  • 3′UTR
  • BRCA1
  • Breast cancer
  • MicroRNAs

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