Clinical significance of large rearrangements in BRCA1 and BRCA2

Thaddeus Judkins, Eric Rosenthal, Christopher Arnell, Lynn Anne Burbidge, Wade Geary, Toby Barrus, Jeremy Schoenberger, Jeffrey Trost, Richard J. Wenstrup, Benjamin B. Roa

Research output: Contribution to journalArticle


Background: Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer. Methods: Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as "high-risk" if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. "Elective" patients did not meet the high-risk criteria, but underwent LR testing as ordered by the referring health care provider. Results: Overall BRCA1/2 mutation prevalence among high-risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high-risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients. Conclusions: Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis. Cancer 2012.

Original languageEnglish (US)
Pages (from-to)5210-5216
Number of pages7
Issue number21
StatePublished - Nov 1 2012



  • BRCA1 gene
  • BRCA2 gene
  • gene rearrangement
  • hereditary breast and ovarian cancer syndrome
  • mutation frequency

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Judkins, T., Rosenthal, E., Arnell, C., Burbidge, L. A., Geary, W., Barrus, T., Schoenberger, J., Trost, J., Wenstrup, R. J., & Roa, B. B. (2012). Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer, 118(21), 5210-5216.