The first two authors contributed equally to this article.
Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary†
Version of Record online: 12 APR 2011
© 2011 Wiley-Liss, Inc.
Volume 32, Issue 6, pages 678–687, June 2011
How to Cite
Whiley, P. J., Guidugli, L., Walker, L. C., Healey, S., Thompson, B. A., Lakhani, S. R., Da Silva, L. M., Investigators, k., Tavtigian, S. V., Goldgar, D. E., Brown, M. A., Couch, F. J. and Spurdle, A. B. (2011), Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary. Hum. Mutat., 32: 678–687. doi: 10.1002/humu.21495
Communicated by Marc S. Greenblatt
- Issue online: 25 MAY 2011
- Version of Record online: 12 APR 2011
- Accepted manuscript online: 10 MAR 2011 11:58AM EST
- Manuscript Accepted: 22 FEB 2011
- Manuscript Received: 15 SEP 2010
- The National Health and Medical Research Council (NHMRC). Grant Number: ID442970
- NIH. Grant Number: CA116167
- NIH Breast Cancer Specialized Program of research Excellence (SPORE). Grant Number: P50 CA116201
- National Breast Cancer Foundation (to kConFab)
- The NHMRC (to kConFab)
- The Queensland Cancer Fund (to kConFab)
- The Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia (to kConFab)
- The Cancer Foundation of Western Australia (to kConFab)
- NHMRC. Grant Numbers: 145684, 288704 (to the kConFab Clinical Follow-Up Study)
- 2009. Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. Eur J Hum Genet 17:1471–1480. , , , , , , , , , .
- 2006. Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Hum Mutat 27:427–435. , , , , , , , .
- kConFab Investigators. 2006. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66:2019–2027. , , , , , , , , , , , , , , , , , , , , , , , , ;
- 2003. Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2. Genes, Chromosomes Cancer 37:314–320. , , , , , , .
- 2008. Assessment of functional effects of unclassified genetic variants. Hum Mutat 29:1314–1326. , , , , , .
- 2009. A deep intronic mutation in FGB creates a consensus exonic splicing enhancer motif that results in afibrinogenemia caused by aberrant mRNA splicing, which can be corrected in vitro with antisense oligonucleotide treatment. Hum Mutat 30:221–227. , , , .
- 2009. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67. , , , , , .
- 2007. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 81:873–883. , , , , , , , , , , .
- 1995. Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am J Hum Genet 57:1284–1297. , , , , , , , , , .
- 2008. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 29:1265–1272. , , , , , .
- 2004. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75:535–544. , , , , , .
- 2001. A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. Hum Mol Genet 10:2679–2686. , , , .
- 1998. Implications of a novel cryptic splice site in the BRCA1 gene. Am J Med Genet 80:140–144. , , , , .
- 2010. The deep intronic c.903+469T>C mutation in the MTRR gene creates an SF2/ASF binding exonic splicing enhancer, which leads to pseudoexon activation and causes the cblE type of homocystinuria. Hum Mutat 31:437–444. , , , , , .
- 2008. Regulation of alternative splicing: more than just the ABCs. J Biol Chem 283:1217–1221. , .
- 2010. Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH. Breast Cancer Res Treat Jul 8 [Epub ahead of print]. , , , , , , .
- 2008. Touchdown PCR for increased specificity and sensitivity in PCR amplification. Nat Protoc 3:1452–1456. , .
- 2008. Characterization of the pathogenic mechanism of a novel BRCA2 variant in a Chinese family. Fam Cancer 7:125–133. , , , , , .
- 1998. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138–1145. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .
- 2002. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310–2318. , , , , , , .
- 1998. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu Rev Genet 32:279–305. .
- 1995. Mutation analysis of the BRCA1 gene in 76 Japanese ovarian cancer patients: four germline mutations, but no evidence of somatic mutation. Hum Mol Genet 4:1953–1956. , , , , , , .
- 2000. A novel insertional mutation and differentially spliced mRNAs in the human BRCA1 gene. Gene Funct Dis 1:38–47. , , .
- 2004. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389–396. , .
- 2002. A new type of mutation causes a splicing defect in ATM. Nat Genet 30:426–429. , , , , , .
- 2008. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29:1282–1291. , , , , , , , , , .
- 1997. Improved splice site detection in Genie. J Comput Biol 4:311–323. , , , .
- 2009. A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance. Hum Mutat 30:1340–1347. , , , , , , .
- 2008. Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer 113:2627–2637. , , , , , , , , , .
- 2008a. Prediction and assessment of splicing alterations: implications for clinical testing. Hum Mutat 29:1304–1313. , , , , .
- kConFab Investigators. 2008b. Clinical classification of BRCA1 and BRCA2 DNA sequence variants: the value of cytokeratin profiles and evolutionary analysis—a report from the kConFab Investigators. J Clin Oncol 26:1657–1663. , , , , , , , , , , , ;
- 2006. The connection between splicing and cancer. J Cell Sci 119(Pt 13):2635–2641. , .
- 2008. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 29:1261–1264. , , , .
- 2003. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73:652–655. , , .
- 2009. Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 30:107–114. , , , , , , , , .
- kConFab Investigators, , , , . 2010. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat 31:E1484–E1505. , , , , , , , , , , , ;
- 2004. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394. , .
- 2008. Dynamic regulation of alternative splicing by silencers that modulate 5′ splice site competition. Cell 135:1224–1236. , , , , , , , , .