Communicated by David E. Goldgar
Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing
Article first published online: 12 DEC 2012
© 2012 Wiley Periodicals, Inc.
Volume 34, Issue 3, pages 439–445, March 2013
How to Cite
Towler, W. I., Zhang, J., Ransburgh, D. J. R., Toland, A. E., Ishioka, C., Chiba, N. and Parvin, J. D. (2013), Analysis of BRCA1 Variants in Double-Strand Break Repair by Homologous Recombination and Single-Strand Annealing. Hum. Mutat., 34: 439–445. doi: 10.1002/humu.22251
Contract grant sponsors: National Institutes of Health (R01 CA141090); The Ohio State University Comprehensive Cancer Center.
- Issue published online: 18 FEB 2013
- Article first published online: 12 DEC 2012
- Accepted manuscript online: 15 NOV 2012 12:30PM EST
- Manuscript Accepted: 24 OCT 2012
- Manuscript Received: 6 JUL 2012
- National Institutes of Health. Grant Number: R01 CA141090
- Ohio State University Comprehensive Cancer Center
- homologous recombination;
- single-strand annealing;
Missense substitutions of uncertain clinical significance in the BRCA1 gene are a vexing problem in genetic counseling for women who have a family history of breast cancer. In this study, we evaluated the functions of 29 missense substitutions of BRCA1 in two DNA repair pathways. Repair of double-strand breaks by homology-directed recombination (HDR) had been previously analyzed for 16 of these BRCA1 variants, and 13 more variants were analyzed in this study. All 29 variants were also analyzed for function in double-strand break repair by the single-strand annealing (SSA) pathway. We found that among the pathogenic mutations in BRCA1, all were defective for DNA repair by either pathway. The HDR assay was accurate because all pathogenic mutants were defective for HDR, and all nonpathogenic variants were fully functional for HDR. Repair by SSA accurately identified pathogenic mutants, but several nonpathogenic variants were scored as defective or partially defective. These results indicated that specific amino acid residues of the BRCA1 protein have different effects in the two related DNA repair pathways, and these results validate the HDR assay as highly correlative with BRCA1-associated breast cancer.