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

Spurdle, Amanda B., Whiley, Phillip J., Thompson, Bryony, Feng, Bingjian, Healey, Sue, Brown, Melissa A., Pettigrew, Christopher, kConFab, Van Asperen, Christi J., Ausems, Margreet G. E. M., Kattentidt-Mouravieva, Anna A., Pigg, Maritta H., Schmutzler, Rita K., Engel, Christoph, Meindl, Alfons, German Consortium of Hereditary Breast and Ovarian Cancer, Caputo, Sandrine, Sinilnikova, Olga M., Lidereau, Rosette, French COVAR group collaborators, Couch, Fergus J., Guidugli, Lucia, van Overeem Hansen, Thomas, Thomassen, Mads, Eccles, Diana M., Tucker, Kathy, Benitez, Javier, Domchek, Susan M., Toland, Amanda E., Van Rensburg, Elizabeth J., Wappenschmidt, Barbara, Borg, Åke, Vreeswijk, Maaike P. G ., Goldgar, David E. and ENIGMA Consortium (2012) BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. Journal of Medical Genetics, 49 8: 525-532. doi:10.1136/jmedgenet-2012-101037

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Author Spurdle, Amanda B.
Whiley, Phillip J.
Thompson, Bryony
Feng, Bingjian
Healey, Sue
Brown, Melissa A.
Pettigrew, Christopher
Van Asperen, Christi J.
Ausems, Margreet G. E. M.
Kattentidt-Mouravieva, Anna A.
Pigg, Maritta H.
Schmutzler, Rita K.
Engel, Christoph
Meindl, Alfons
German Consortium of Hereditary Breast and Ovarian Cancer
Caputo, Sandrine
Sinilnikova, Olga M.
Lidereau, Rosette
French COVAR group collaborators
Couch, Fergus J.
Guidugli, Lucia
van Overeem Hansen, Thomas
Thomassen, Mads
Eccles, Diana M.
Tucker, Kathy
Benitez, Javier
Domchek, Susan M.
Toland, Amanda E.
Van Rensburg, Elizabeth J.
Wappenschmidt, Barbara
Borg, Åke
Vreeswijk, Maaike P. G .
Goldgar, David E.
ENIGMA Consortium
Total Author Count Override 33
Title BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk
Journal name Journal of Medical Genetics   Check publisher's open access policy
ISSN 0022-2593
Publication date 2012-08
Sub-type Article (original research)
DOI 10.1136/jmedgenet-2012-101037
Volume 49
Issue 8
Start page 525
End page 532
Total pages 8
Place of publication London, United Kingdom
Publisher BMJ
Collection year 2013
Language eng
Formatted abstract
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.
Keyword Breast cancer
Genetic counselling
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 28 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 29 times in Scopus Article | Citations
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Created: Wed, 03 Oct 2012, 09:14:53 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences