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Åke Borg

Åke Borg

Principal investigator

Åke Borg

BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk


  • Amanda B. Spurdle
  • Phillip J. Whiley
  • Bryony Thompson
  • Bingjian Feng
  • Sue Healey
  • Melissa A. Brown
  • Christopher Pettigrew
  • Christi J. Van Asperen
  • Margreet G. E. M. Ausems
  • Anna A. Kattentidt-Mouravieva
  • Ans M. W. van den Ouweland
  • Annika Lindblom
  • Maritta H. Pigg
  • Rita K. Schmutzler
  • Christoph Engel
  • Alfons Meindl
  • Sandrine Caputo
  • Olga M. Sinilnikova
  • Rosette Lidereau
  • Fergus J. Couch
  • Lucia Guidugli
  • Thomas van Overeem Hansen
  • Mads Thomassen
  • Diana M. Eccles
  • Kathy Tucker
  • Javier Benitez
  • Susan M. Domchek
  • Amanda E. Toland
  • Elizabeth J. Van Rensburg
  • Barbara Wappenschmidt
  • Åke Borg
  • Maaike P. G. Vreeswijk
  • David E. Goldgar

Summary, in English

Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less 'BRCA1-like' than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more 'BRCA1-like' than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G>A p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.


  • Breastcancer-genetics
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year







Journal of Medical Genetics





Document type

Journal article


BMJ Publishing Group


  • Medical Genetics




  • ISSN: 0022-2593