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. CouchLucia Guidugli, Thomas van Overeem Hansen, Mads Thomassen, Diana M. Eccles, Kathy Tucker, Javier Benitez, Susan M. Domchek, Amanda E. Toland, J Van Rensburg Elizabeth J Van Rensburg, Barbara Wappenschmidt, Åke Borg, Maaike P.G. Vreeswijk, David E. Goldgar, Frans B. Hogervorst, Rogier A. Oldenburg, Juul T. Wijnen, Peter Devilee, Rob B. van der Luijt, Johan J.P. Gille, Muriel A. Adank, Encarna B. Gomez Garcia, Marinus J. Blok, Jan C. Oosterwijk, A. H. van der Hout, Genevieve Michils, Eric Legius, Erik Teugels, de Grève Jacques de Grève, Norbert Arnold, Helmut Deisler, Dorothea Gadzicki, Andrea Gehrig, Wolfram Heinritz, Karin Kast, Dieter Niederacher, Sabine Preisler-Adams, Christian Sutter, Raymonda Varon-Mateeva, Bernhard H. Weber, Nicolas Sévenet, Françoise Bonnet, Michel Longy, Agnès Hardouin, Dominique Vaur, Sophie Krieger, Nancy Uhrhammer, Yves Jean Bignon, Jean Philippe Peyrat, Françoise Revillion, Joëlle Fournier, Sylvie Mazoyer, Mélanie Léone, Hagay Sobol, Tetsuro Noguchi, Violaine Bourdon, Audrey Remenieras, Jean Marc Rey, Myriam Bronner, Joanna Sokolowska-Gillois, Philippe Jonveaux, Capucine Delnatte, Florence Coulet, Laurent Castera, Virginie Caux-Moncoutier, Claude Houdayer, Stoppa-Lyonnet Dominique Stoppa-Lyonnet, Chantal Delvincourt, Marie Claude Gorisse, Ivan Bièche, Cédrick Lefol, Etienne Rouleau, Joseph Abecassis, Danièle Muller, Christine Toulas, Marine Guillaud-Bataille, Brigitte Bressac-de Paillerets, Richard Barber, Tina Bedenham, Lucy Burgess, Joanna Campbell, Jackie Cook, Andrew Devereau, Bent Ejlertsen, Mike Fields, Anne Marie Gerdes, Elizabeth Johnston, Torben A. Kruse, Anita Luharia, Carole Mckeown, Kate Nathanson, Finn C. Nielsen, Leigha Senter, Barbara Stayner, Kevin Sweet, Simon Thomas, Yvonne Wallis, Sally Watts

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalJournal of medical genetics
Issue number8
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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