Multimodel assessment of BRCA1 mutations in Taiwanese (ethnic Chinese) women with early-onset, bilateral or familial breast cancer

J Hum Genet. 2012 Feb;57(2):130-8. doi: 10.1038/jhg.2011.142. Epub 2012 Jan 26.


Although evidence suggests an importance of genetic factors in the development of breast cancer in Taiwanese (ethnic Chinese) women, including a high incidence of early-onset and secondary contralateral breast cancer, a major breast cancer predisposition gene, BRCA1, has not been well studied in this population. In fact, the carcinogenic impacts of many genetic variants of BRCA1 are unknown and classified as variants of uncertain significance (VUS). It is therefore important to establish a method to characterize the BRCA1 VUSs and understand their role in Taiwanese breast cancer patients. Accordingly, we developed a multimodel assessment strategy consisting of a prescreening portion and a validated functional assay to study breast cancer patients with early-onset, bilateral or familial breast cancer. We found germ-line BRCA1 mutations in 11.1% of our cohort and identified one novel missense mutation, c.5191C>A. Two genetic variants were initially classified as VUSs (c.1155C>T and c.5191C>A). c.1155C>T is not predicted to be deleterious in the prescreening portion of our assessment strategy. c.5191C>A, on the other hand, causes p.T1691K, which is predicted to have high deleterious probability because of significant structural alteration, a high deleterious score in the predictive programs and, clinically, triple negative characteristics in breast tumors. This mutant is confirmed by transcription activation and yeast growth-inhibition assays. In conclusion, we show as high a prevalence of germ-line BRCA1 mutation in high-risk Taiwanese patients as in Caucasians and demonstrate a useful strategy for studying BRCA1 VUSs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Motifs
  • Asian Continental Ancestry Group*
  • BRCA1 Protein / biosynthesis
  • BRCA1 Protein / chemistry
  • BRCA1 Protein / genetics*
  • Base Sequence
  • Breast Neoplasms / ethnology
  • Breast Neoplasms / genetics*
  • Carcinoma, Ductal, Breast / ethnology
  • Carcinoma, Ductal, Breast / genetics*
  • Computational Biology
  • DNA Mutational Analysis
  • Female
  • Genetic Association Studies
  • Germ-Line Mutation
  • HEK293 Cells
  • Humans
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Sequence Alignment
  • Taiwan


  • BRCA1 Protein
  • BRCA1 protein, human
  • Recombinant Fusion Proteins