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

Hum Mutat. 2012 Dec;33(12):1665-75. doi: 10.1002/humu.22159. Epub 2012 Aug 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions*
  • Adult
  • BRCA1 Protein / genetics*
  • Base Pairing
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Cell Line, Tumor
  • Conserved Sequence
  • DNA Mutational Analysis
  • ELAV Proteins
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Frequency
  • Genetic Association Studies
  • Germ-Line Mutation*
  • Humans
  • MicroRNAs / genetics*
  • Nucleic Acid Conformation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • RNA Interference
  • RNA, Messenger / genetics


  • 3' Untranslated Regions
  • BRCA1 Protein
  • BRCA1 protein, human
  • ELAV Proteins
  • MIRN103 microRNA, human
  • MicroRNAs
  • RNA, Messenger