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

Human Mutation

Volumn 32, Issue 6, 2011, Pages 678-687

  Whiley, Phillip J ^a,b   Guidugli, Lucia ^c   Walker, Logan C ^a   Healey, Sue ^a   Thompson, Bryony A ^a   Lakhani, Sunil R ^d   Da Silva, Leonard M ^d   Investigators, Kconfab ^e   Tavtigian, Sean V ^f   Goldgar, David E ^g   Brown, Melissa A ^b   Couch, Fergus J ^c   Spurdle, Amanda B ^a  

^a QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^b UNIVERSITY OF QUEENSLAND   (Australia)

^c MAYO CLINIC   (United States)

^d UNIVERSITY OF QUEENSLAND   (Australia)

^e PETER MACCALLUM CANCER CENTRE   (Australia)

^f UNIVERSITY OF UTAH   (United States)

^g UNIVERSITY OF UTAH SCHOOL OF MEDICINE   (United States)

Author keywords

BRCA1; BRCA2; Clinical significance; Variants

Indexed keywords

BRCA1 PROTEIN; BRCA2 PROTEIN; DINUCLEOTIDE;

ARTICLE; CLINICAL ARTICLE; COMPUTER MODEL; EXON; FACTORIAL ANALYSIS; GENE SEQUENCE; GENETIC VARIABILITY; HUMAN; IN VITRO STUDY; INTRON; LYMPHOBLASTOID CELL; PATHOGENICITY; PRIORITY JOURNAL; RNA SPLICING;

ALTERNATIVE SPLICING; BRCA1 PROTEIN; BRCA2 PROTEIN; BREAST NEOPLASMS; CELL LINE, TUMOR; COMPUTATIONAL BIOLOGY; EXONS; FEMALE; GENETIC VARIATION; HUMANS; INTRONS; MUTATION; RNA, MESSENGER;

EID: 79957603664     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.21495     Document Type: Article

References (38)

1. Caux-Moncoutier V, Pages-Berhouet S, Michaux D, Asselain B, Castera L, De Pauw A, Buecher B, Gauthier-Villars M, Stoppa-Lyonnet D, Houdayer C. 2009. Impact of BRCA1 and BRCA2 variants on splicing: clues from an allelic imbalance study. Eur J Hum Genet 17:1471-1480.
2. Chen X, Truong T-TN, Weaver J, Bove BA, Cattie K, Armstrong BA, Daly MB, Godwin AK. 2006. Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Hum Mutat 27:427-435.
3. Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, Tavtigian SV, Goldgar D, Spurdle AB; Kconfab Investigators. 2006. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66:2019-2027.
4. Claes K, Poppe B, Machackova E, Coene I, Foretova L, De Paepe A, Messiaen L. 2003. Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2. Genes, Chromosomes Cancer 37:314-320.
5. Couch FJ, Rasmussen LJ, Hofstra R, Monteiro AN, Greenblatt MS, de Wind N. 2008. Assessment of functional effects of unclassified genetic variants. Hum Mutat 29:1314-1326.
6. Davis RL, Homer VM, George PM, Brennan SO. 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.
7. Desmet FO, Hamroun D, Lalande M, Collod-Beroud G, Claustres M, Beroud C. 2009. Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37:e67.
8. Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, Tavtigian SV, Monteiro AN, Iversen ES, Couch FJ, Goldgar DE. 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.
9. Friedman LS, Szabo CI, Ostermeyer EA, Dowd P, Butler L, Park T, Lee MK, Goode EL, Rowell SE, King MC. 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.
10. Goldgar DE, Easton DF, Byrnes GB, Spurdle AB, Iversen ES, Greenblatt MS. 2008. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 29:1265-1272.
11. Goldgar DE, Easton DF, Deffenbaugh AM, Monteiro ANA, Tavtigian SV, Couch FJ. 2004. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75:535-544.
12. Harland M, Mistry S, Bishop DT, Bishop JA. 2001. A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees. Hum Mol Genet 10:2679-2686.
13. Hoffman JD, Hallam SE, Venne VL, Lyon E, Ward K. 1998. Implications of a novel cryptic splice site in the BRCA1 gene. Am J Med Genet 80:140-144.
14. Homolova K, Zavadakova P, Doktor TK, Schroeder LD, Kozich V, Andresen BS. 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.
15. House AE, Lynch KW. 2008. Regulation of alternative splicing: more than just the ABCs. J Biol Chem 283:1217-1221.
16. Joosse SA, Brandwijk KI, Devilee P, Wesseling J, Hogervorst FB, Verhoef S, Nederlof PM. 2010. Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH. Breast Cancer Res Treat Jul 8 [Epub ahead of print].
17. Korbie DJ, Mattick JS. 2008. Touchdown PCR for increased specificity and sensitivity in PCR amplification. Nat Protoc 3:1452-1456.
18. Kwong A, Wong LP, Chan KY, Ma ES, Khoo US, Ford JM. 2008. Characterization of the pathogenic mechanism of a novel BRCA2 variant in a Chinese family. Fam Cancer 7:125-133.
19. Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, Farid LM, Venter D, Antoniou A, Storfer-Isser A, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Ford D, Peto J, Stoppa-Lyonnet D, Bignon YJ, Struewing JP, Spurr NK, Bishop DT, Klijn JG, Devilee P, Cornelisse CJ, Lasset C, Lenoir G, Barkardottir RB, Egilsson V, Hamann U, Chang-Claude J, Sobol H, Weber B, Stratton MR, Easton DF. 1998. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90:1138-1145.
20. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF. 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.
21. Lopez AJ. 1998. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu Rev Genet 32:279-305.
22. Matsushima M, Kobayashi K, Emi M, Saito H, Saito J, Suzumori K, Nakamura Y. 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.
23. Munnes M, Zuther I, Schmitz B. 2000. A novel insertional mutation and differentially spliced mRNAs in the human BRCA1 gene. Gene Funct Dis 1:38-47.
24. Pagani F, Baralle FE. 2004. Genomic variants in exons and introns: identifying the splicing spoilers. Nat Rev Genet 5:389-396.
25. Pagani F, Buratti E, Stuani C, Bendix R, Dork T, Baralle FE. 2002. A new type of mutation causes a splicing defect in ATM. Nat Genet 30:426-429.
26. Plon SE, Eccles DM, Easton D, Foulkes WD, Genuardi M, Greenblatt MS, Hogervorst FB, Hoogerbrugge N, Spurdle AB, Tavtigian SV. 2008. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29:1282-1291.
27. Reese MG, Eeckman FH, Kulp D, Haussler D. 1997. Improved splice site detection in Genie. J Comput Biol 4:311-323.
28. Rio Frio T, McGee TL, Wade NM, Iseli C, Beckmann JS, Berson EL, Rivolta C. 2009. A single-base substitution within an intronic repetitive element causes dominant retinitis pigmentosa with reduced penetrance. Hum Mutat 30:1340-1347.
29. Schwartz GF, Hughes KS, Lynch HT, Fabian CJ, Fentiman IS, Robson ME, Domchek SM, Hartmann LC, Holland R, Winchester DJ. 2008. Proceedings of the international consensus conference on breast cancer risk, genetics, & risk management, April, 2007. Cancer 113:2627-2637.
30. Spurdle AB, Couch FJ, Hogervorst FB, Radice P, Sinilnikova OM. 2008a. Prediction and assessment of splicing alterations: implications for clinical testing. Hum Mutat 29:1304-1313.
31. Spurdle AB, Lakhani SR, Healey S, Parry S, Da Silva LM, Brinkworth R, Hopper JL, Brown MA, Babikyan D, Chenevix-Trench G, Tavtigian SV, Goldgar DE; 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.
32. Srebrow A, Kornblihtt AR. 2006. The connection between splicing and cancer. J Cell Sci 119(Pt 13):2635-2641.
33. Tavtigian SV, Greenblatt MS, Goldgar DE, Boffetta P. 2008. Assessing pathogenicity: overview of results from the IARC Unclassified Genetic Variants Working Group. Hum Mutat 29:1261-1264.
34. Thompson D, Easton DF, Goldgar DE. 2003. A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73:652-655.
35. Vreeswijk MP, Kraan JN, van der Klift HM, Vink GR, Cornelisse CJ, Wijnen JT, Bakker E, van Asperen CJ, Devilee P. 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.
36. Walker LC, Whiley PJ, Couch FJ, Farrugia DJ, Healey S, Eccles DM, Lin F, Butler SA, Goff SA, Thompson BA, Lakhani SR, Da Silva LM; Kconfab Investigators, Tavtigian SV, Goldgar DE, Brown MA, Spurdle AB. 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.
37. Yeo G, Burge CB. 2004. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377-394.
38. Yu Y, Maroney PA, Denker JA, Zhang XH, Dybkov O, Luhrmann R, Jankowsky E, Chasin LA, Nilsen TW. 2008. Dynamic regulation of alternative splicing by silencers that modulate 5' splice site competition. Cell 135:1224-1236.