RT Journal Article
SR Electronic
T1 BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 525
OP 532
DO 10.1136/jmedgenet-2012-101037
VO 49
IS 8
A1 Amanda B Spurdle
A1 Phillip J Whiley
A1 Bryony Thompson
A1 Bingjian Feng
A1 Sue Healey
A1 Melissa A Brown
A1 Christopher Pettigrew
A1 kConFab
A1 Christi J Van Asperen
A1 Margreet G E M Ausems
A1 Anna A Kattentidt-Mouravieva
A1 Ans M W van den Ouweland
A1 Dutch Belgium UV Consortium
A1 Annika Lindblom
A1 Maritta H Pigg
A1 Rita K Schmutzler
A1 Christoph Engel
A1 Alfons Meindl
A1 German Consortium of Hereditary Breast and Ovarian Cancer
A1 Sandrine Caputo
A1 Olga M Sinilnikova
A1 Rosette Lidereau
A1 French COVAR group collaborators
A1 Fergus J Couch
A1 Lucia Guidugli
A1 Thomas van Overeem Hansen
A1 Mads Thomassen
A1 Diana M Eccles
A1 Kathy Tucker
A1 Javier Benitez
A1 Susan M Domchek
A1 Amanda E Toland
A1 Elizabeth J Van Rensburg
A1 Barbara Wappenschmidt
A1 Åke Borg
A1 Maaike P G Vreeswijk
A1 David E Goldgar
YR 2012
UL http://jmg.bmj.com/content/49/8/525.abstract
AB 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.