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, Elizabeth J. Van Rensburg, Barbara Wappenschmidt, Ake Borg, Maaike P. G. Vreeswijk, David E. Goldgar, kConFab, Dutch Belgium UV Consortium, German Consortium Hereditary, French COVAR Grp Collaborators, ENIGMA Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

65 Citations (Scopus)

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 (pA 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
Pages (from-to)525-532
Number of pages8
JournalJOURNAL OF MEDICAL GENETICS
Volume49
Issue number8
DOIs
Publication statusPublished - Aug-2012

Keywords

  • UNKNOWN CLINICAL-SIGNIFICANCE
  • DNA-SEQUENCE VARIANTS
  • MISSENSE SUBSTITUTIONS
  • GENETIC SUSCEPTIBILITY
  • UNCERTAIN SIGNIFICANCE
  • UNCLASSIFIED VARIANTS
  • SPLICING ABERRATIONS
  • FAMILY-HISTORY
  • BOADICEA MODEL
  • CLASSIFICATION

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