Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: The WECARE study

Åke Borg, Robert W. Haile, Kathleen E. Malone, Marinela Capanu, Ahn Diep, Therese Törngren, Sharon Teraoka, Colin B. Begg, Duncan C. Thomas, Patrick Concannon, Lene Mellemkjaer, Leslie Bernstein, Lina Tellhed, Shanyan Xue, Eric R. Olson, Xiaolin Liang, Jessica Dolle, Anne Lise Børresen-Dale, Jonine L. Bernstein, Anne S. ReinerTracy M. Layne, Laura Donnelly-Allen, Jørgen H. Olsen, Michael Andersson, Lisbeth Bertelsen, Per Guldberg, Noemi Epstein, John D. Boice, Daniela Seminara, Roy E. Shore, Laila Jansen, Hoda Anton-Culver, Joan Largent, Charles F. Lynch, Jeanne DeWall, Bryan M. Langholz, Nianmin Zhou, Anh T. Diep, Evgenia Ter-Karapetova, W. Douglas Thompson, Marilyn Stovall, Susan Smith, Nirasha Ramchurren

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.

Original languageEnglish
Pages (from-to)E1200-E1240
JournalHuman Mutation
Volume31
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

Keywords

  • BRCA1
  • BRCA2
  • Breast cancer
  • Contralateral
  • Deleterious mutation
  • Risk
  • Unclassified variants

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