Adding In Silico Assessment of Potential Splice Aberration to the Integrated Evaluation of BRCA Gene Unclassified Variants

Human Mutation

Volumn 37, Issue 7, 2016, Pages 627-639

  Vallée, Maxime P ^a   Di Sera, Tonya L ^b   Nix, David A ^c   Paquette, Andrew M ^d   Parsons, Michael T ^e   Bell, Russel ^d   Hoffman, Andrea ^e   Hogervorst, Frans B L ^f   Goldgar, David E ^d   Spurdle, Amanda B ^e   Tavtigian, Sean V ^d  

^a University Laval   (Canada)

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

^c ARUP LABORATORIES   (United States)

^d UNIVERSITY OF UTAH   (United States)

^e QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^f NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

BRCA1; BRCA2; cancer predisposition; rare variant; unclassified variant; variant of uncertain significance

Indexed keywords

ARTICLE; BRCA GENE; CALIBRATION; COMPUTER MODEL; CONSENSUS SEQUENCE; DATA BASE; EVALUATION STUDY; EXON; GENE; GENE SEQUENCE; GENETIC VARIATION; MISSENSE MUTATION; NUCLEIC ACID BASE SUBSTITUTION; PRIORITY JOURNAL; PROBABILITY; RISK ASSESSMENT; SEQUENCE ANALYSIS; WILD TYPE;

EID: 84974687831     PISSN: 10597794     EISSN: 10981004     Source Type: Journal    
DOI: 10.1002/humu.22973     Document Type: Article

References (95)

1. Acedo A, Sanz DJ, Duran M, Infante M, Perez-Cabornero L, Miner C, Velasco EA. 2012. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. Breast Cancer Res 14:R87.
2. Acedo A, Hernandez-Moro C, Curiel-Garcia A, Diez-Gomez B, Velasco EA. 2015. Functional classification of BRCA2 DNA variants by splicing assays in a large minigene with 9 exons. Hum Mutat 36:210–221.
3. Agata S, De Nicolo A, Chieco-Bianchi L, D'Andrea E, Menin C, Montagna M. 2003. The BRCA2 sequence variant IVS19+1G→A leads to an aberrant transcript lacking exon 19. Cancer Genet Cytogenet 141:175–176.
4. Ahlborn LB, Dandanell M, Steffensen AY, Jonson L, Nielsen FC, Hansen TV. 2015. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic. Breast Cancer Res Treat 150:289–298.
5. Anczukow O, Buisson M, Salles MJ, Triboulet S, Longy M, Lidereau R, Sinilnikova OM, Mazoyer S. 2008. Unclassified variants identified in BRCA1 exon 11: consequences on splicing. Genes Chromosomes Cancer 47:418–426.
6. Ang P, Lim IH, Lee TC, Luo JT, Ong DC, Tan PH, Lee AS. 2007. BRCA1 and BRCA2 mutations in an Asian clinic-based population detected using a comprehensive strategy. Cancer Epidemiol Biomarkers Prev 16:2276–2284.
7. Beristain E, Martinez-Bouzas C, Guerra I, Viguera N, Moreno J, Ibanez E, Diez J, Rodriguez F, Mallabiabarrena G, Lujan S, Gorostiaga J, De Pablo JL, et al. 2007. Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling. Breast Cancer Res Treat 106:255–262.
8. Bonatti F, Pepe C, Tancredi M, Lombardi G, Aretini P, Sensi E, Falaschi E, Cipollini G, Bevilacqua G, Caligo MA. 2006. RNA-based analysis of BRCA1 and BRCA2 gene alterations. Cancer Genet Cytogenet 170:93–101.
9. Bonnet C, Krieger S, Vezain M, Rousselin A, Tournier I, Martins A, Berthet P, Chevrier A, Dugast C, Layet V, Rossi A, Lidereau R, et al. 2008. Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene. J Med Genet 45:438–446.
10. Brandao RD, van Roozendaal K, Tserpelis D, Gomez Garcia E, Blok MJ. 2011. Characterisation of unclassified variants in the BRCA1/2 genes with a putative effect on splicing. Breast Cancer Res Treat 129:971–982.
11. Brose MS, Volpe P, Paul K, Stopfer JE, Colligon TA, Calzone KA, Weber BL. 2004. Characterization of two novel BRCA1 germ-line mutations involving splice donor sites. Genet Test 8:133–138.
12. Buratti E, Chivers M, Hwang G, Vorechovsky I. 2011. DBASS3 and DBASS5: databases of aberrant 3’- and 5’-splice sites. Nucleic Acids Res 39:D86–D91.
13. Campos B, Diez O, Domenech M, Baena M, Balmana J, Sanz J, Ramirez A, Alonso C, Baiget M. 2003. RNA analysis of eight BRCA1 and BRCA2 unclassified variants identified in breast/ovarian cancer families from Spain. Hum Mutat 22:337.
14. 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.
15. Chen X, Truong TT, 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.
16. 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, et al. 2006. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66:2019–2027.
17. Claes K, Vandesompele J, Poppe B, Dahan K, Coene I, De Paepe A, Messiaen L. 2002. Pathological splice mutations outside the invariant AG/GT splice sites of BRCA1 exon 5 increase alternative transcript levels in the 5’ end of the BRCA1 gene. Oncogene 21:4171–4175.
18. 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.
19. Colombo M, De Vecchi G, Caleca L, Foglia C, Ripamonti CB, Ficarazzi F, Barile M, Varesco L, Peissel B, Manoukian S, Radice P. 2013. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One 8:e57173.
20. Colombo M, Blok MJ, Whiley P, Santamarina M, Gutierrez-Enriquez S, Romero A, Garre P, Becker A, Smith LD, De Vecchi G, Brandao RD, Tserpelis D, et al. 2014. Comprehensive annotation of splice junctions supports pervasive alternative splicing at the BRCA1 locus: a report from the ENIGMA consortium. Hum Mol Genet 23:3666–3680.
21. de Garibay GR, Acedo A, Garcia-Casado Z, Gutierrez-Enriquez S, Tosar A, Romero A, Garre P, Llort G, Thomassen M, Diez O, Perez-Segura P, Diaz-Rubio E, et al. 2014. Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants. Hum Mutat 35:53–57.
22. Di Giacomo D, Gaildrat P, Abuli A, Abdat J, Frebourg T, Tosi M, Martins A. 2013. Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. Hum Mutat 34:1547–1557.
23. Domchek SM, Tang J, Stopfer J, Lilli DR, Hamel N, Tischkowitz M, Monteiro AN, Messick TE, Powers J, Yonker A, Couch FJ, Goldgar DE, Davidson HR, Nathanson KL, Foulkes WD, Greenberg RA. 2013. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov 3:399–405.
24. Dosil V, Tosar A, Canadas C, Perez-Segura P, Diaz-Rubio E, Caldes T, de la Hoya M. 2010. Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study. Clin Chem 56:53–61.
25. 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.
26. Fackenthal JD, Cartegni L, Krainer AR, Olopade OI. 2002. BRCA2 T2722R is a deleterious allele that causes exon skipping. Am J Hum Genet 71:625–631.
27. Farrugia DJ, Agarwal MK, Pankratz VS, Deffenbaugh AM, Pruss D, Frye C, Wadum L, Johnson K, Mentlick J, Tavtigian SV, Goldgar DE, Couch FJ. 2008. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res 68:3523–3531.
28. Fetzer S, Tworek HA, Piver MS, DiCioccio RA. 1999. Classification of IVS1-10T→C as a polymorphism of BRCA1. Cancer Genet Cytogenet 113:58–64.
29. Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, King MC. 1994. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 8:399–404.
30. 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.
31. Gaildrat P, Krieger S, Thery JC, Killian A, Rousselin A, Berthet P, Frebourg T, Hardouin A, Martins A, Tosi M. 2010. The BRCA1 c.5434C→G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet 47:398–403.
32. Gaildrat P, Krieger S, Di Giacomo D, Abdat J, Revillion F, Caputo S, Vaur D, Jamard E, Bohers E, Ledemeney D, Peyrat JP, Houdayer C, et al. 2012. Multiple sequence variants of BRCA2 exon 7 alter splicing regulation. J Med Genet 49:609–617.
33. Gayther SA, Warren W, Mazoyer S, Russell PA, Harrington PA, Chiano M, Seal S, Hamoudi R, van Rensburg EJ, Dunning AM, Love R, Evans G, et al. 1995. Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nat Genet 11:428–433.
34. Goina E, Skoko N, Pagani F. 2008. Binding of DAZAP1 and hnRNPA1/A2 to an exonic splicing silencer in a natural BRCA1 exon 18 mutant. Mol Cell Biol 28:3850–3860.
35. Goldgar DE, Easton DF, Deffenbaugh AM, Monteiro AN, 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.
36. 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.
37. Gutierrez-Enriquez S, Coderch V, Masas M, Balmana J, Diez O. 2009. The variants BRCA1 IVS6-1G>A and BRCA2 IVS15+1G>A lead to aberrant splicing of the transcripts. Breast Cancer Res Treat 117:461–465.
38. Hansen TV, Steffensen AY, Jonson L, Andersen MK, Ejlertsen B, Nielsen FC. 2010. The silent mutation nucleotide 744 G → A, Lys172Lys, in exon 6 of BRCA2 results in exon skipping. Breast Cancer Res Treat 119:547–550.
39. Hartikainen JM, Pirskanen MM, Arffman AH, Ristonmaa UK, Mannermaa AJ. 2000. A Finnish BRCA1 exon 12 4216-2nt A to G splice acceptor site mutation causes aberrant splicing and frameshift, leading to protein truncation. Hum Mutat 15:120.
40. 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.
41. Hofmann W, Horn D, Huttner C, Classen E, Scherneck S. 2003. The BRCA2 variant 8204G>A is a splicing mutation and results in an in frame deletion of the gene. J Med Genet 40:e23.
42. Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Leone M, et al. 2012. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat 33:1228–1238.
43. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, et al. 2002. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609.
44. Jian X, Boerwinkle E, Liu X. 2014. In silico prediction of splice-altering single nucleotide variants in the human genome. Nucleic Acids Res 42:13534–13544.
45. Joosse SA, Brandwijk KI, Devilee P, Wesseling J, Hogervorst FB, Verhoef S, Nederlof PM. 2012. Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH. Breast Cancer Res Treat 132:379–389.
46. Keaton JC, Nielsen DR, Hendrickson BC, Pyne MT, Scheuer L, Ward BE, Brothman AR, Scholl T. 2003. A biochemical analysis demonstrates that the BRCA1 intronic variant IVS10-2A→ C is a mutation. J Hum Genet 48:399–403.
47. Krajc M, De Greve J, Goelen G, Teugels E. 2002. BRCA2 founder mutation in Slovenian breast cancer families. Eur J Hum Genet 10:879–882.
48. 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.
49. Laskie Ostrow K, DiCioccio RA, McGuire V, Whittemore AS. 2001. A BRCA1 variant, IVS23+1G→A, causes abnormal RNA splicing by deleting exon 23. Cancer Genet Cytogenet 127:188–190.
50. Li L, Biswas K, Habib LA, Kuznetsov SG, Hamel N, Kirchhoff T, Wong N, Armel S, Chong G, Narod SA, Claes K, Offit K, et al. 2009. Functional redundancy of exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A>G (p.I2285V) variant. Hum Mutat 30:1543–1550.
51. Lindor NM, Guidugli L, Wang X, Vallee MP, Monteiro AN, Tavtigian S, Goldgar DE, Couch FJ. 2012. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat 33:8–21.
52. Lunter G, Hein J. 2004. A nucleotide substitution model with nearest-neighbour interactions. Bioinformatics 20 Suppl 1:i216–i223.
53. Machackova E, Foretova L, Lukesova M, Vasickova P, Navratilova M, Coene I, Pavlu H, Kosinova V, Kuklova J, Claes K. 2008. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer 8:140.
54. Mazoyer S, Puget N, Perrin-Vidoz L, Lynch HT, Serova-Sinilnikova OM, Lenoir GM. 1998. A BRCA1 nonsense mutation causes exon skipping. Am J Hum Genet 62:713–715.
55. Menendez M, Castellsague J, Mirete M, Pros E, Feliubadalo L, Osorio A, Calaf M, Tornero E, del Valle J, Fernandez-Rodriguez J, Quiles F, Salinas M, Velasco A, Teule A, Brunet J, Blanco I, Capella G, Lazaro C. 2012. Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 132:979–992.
56. Meindl A. 2002. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 97:472–480.
57. Ozcelik H, Nedelcu R, Chan VW, Shi XH, Murphy J, Rosen B, Andrulis IL. 1999. Mutation in the coding region of the BRCA1 gene leads to aberrant splicing of the transcript. Hum Mutat 14:540–541.
58. Parsons MT, Whiley PJ, Beesley J, Drost M, de Wind N, Thompson BA, Marquart L, Hopper JL, Jenkins MA, Brown MA, Tucker K, Warwick L, et al. 2013. Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: use of potential alternative start sites and implications for predicting variant pathogenicity. Mol Carcinog 54:513–522.
59. Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drusedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, et al. 1997. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345.
60. 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.
61. Pyne MT, Pruss D, Ward BE, Scholl T. 1999. A characterization of genetic variants in BRCA1 intron 8 identifies a mutation and a polymorphism. Mutat Res 406:101–107.
62. Pyne MT, Brothman AR, Ward B, Pruss D, Hendrickson BC, Scholl T. 2000. The BRCA2 genetic variant IVS7 + 2T→G is a mutation. J Hum Genet 45:351–357.
63. Rosenthal ET, Bowles KR, Pruss D, van Kan A, Vail PJ, McElroy H, Wenstrup RJ. 2015. Exceptions to the rule: case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes. Clin Genet 88:533–541.
64. Rouleau E, Lefol C, Moncoutier V, Castera L, Houdayer C, Caputo S, Bieche I, Buisson M, Mazoyer S, Stoppa-Lyonnet D, Nogues C, Lidereau R. 2010. A missense variant within BRCA1 exon 23 causing exon skipping. Cancer Genet Cytogenet 202:144–146.
65. Santarosa M, Viel A, Boiocchi M. 1999. Splice variant lacking the transactivation domain of the BRCA2 gene and mutations in the splice acceptor site of intron 2. Genes Chromosomes Cancer 26:381–382.
66. Santos C, Peixoto A, Rocha P, Pinto P, Bizarro S, Pinheiro M, Pinto C, Henrique R, Teixeira MR. 2014. Pathogenicity evaluation of BRCA1 and BRCA2 unclassified variants identified in Portuguese breast/ovarian cancer families. J Mol Diagn 16:324–334.
67. Sanz DJ, Acedo A, Infante M, Duran M, Perez-Cabornero L, Esteban-Cardenosa E, Lastra E, Pagani F, Miner C, Velasco EA. 2010. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res 16:1957–1967.
68. Scholl T, Pyne MT, Russo D, Ward BE. 1999. BRCA1 IVS16+6T→C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site. Am J Med Genet 85:113–116.
69. Sharp A, Pichert G, Lucassen A, Eccles D. 2004. RNA analysis reveals splicing mutations and loss of expression defects in MLH1 and BRCA1. Hum Mutat 24:272.
70. Spearman AD, Sweet K, Zhou XP, McLennan J, Couch FJ, Toland AE. 2008. Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 26:5393–5400.
71. Spurdle AB. 2010. Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models. Curr Opin Genet Dev 20:315–323.
72. Starita LM, Young DL, Islam M, Kitzman JO, Gullingsrud J, Hause RJ, Fowler DM, Parvin JD, Shendure J, Fields S. 2015. Massively parallel functional analysis of BRCA1 RING domain variants. Genetics 200:413–422.
73. Steffensen AY, Jonson L, Ejlertsen B, Gerdes AM, Nielsen FC, Hansen TV. 2010. Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations. FAM Cancer 9:283–287.
74. Tavtigian SV, Byrnes GB, Goldgar DE, Thomas A. 2008. Classification of rare missense substitutions, using risk surfaces, with genetic- and molecular-epidemiology applications. Hum Mutat 29:1342–1354.
75. Tesoriero AA, Wong EM, Jenkins MA, Hopper JL, Brown MA, Chenevix-Trench G, Spurdle AB, Southey MC. 2005. Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. Hum Mutat 26:495.
76. Thery JC, Krieger S, Gaildrat P, Revillion F, Buisine MP, Killian A, Duponchel C, Rousselin A, Vaur D, Peyrat JP, Berthet P, Frebourg T, Martins A, Hardouin A, Tosi M. 2011. Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes. Eur J Hum Genet 19:1052–1058.
77. Thomassen M, Blanco A, Montagna M, Hansen TV, Pedersen IS, Gutierrez-Enriquez S, Menendez M, Fachal L, Santamarina M, Steffensen AY, Jonson L, Agata S, et al. 2012. Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. Breast Cancer Res Treat 132:1009–1023.
78. Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, Parsons MT, Michael DW, Gallinger S, Haile RW, Hopper JL, Jenkins MA, et al. 2013a. A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the colon cancer family registry. Hum Mutat 34:200–209.
79. Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, et al. 2013b. Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. Hum Mutat 34:255–265.
80. Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capella G, den Dunnen JT, du Sart D, Fabre A, et al. 2014. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46:107–115.
81. Vallee MP, Francy TC, Judkins MK, Babikyan D, Lesueur F, Gammon A, Goldgar DE, Couch FJ, Tavtigian SV. 2012. Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs. Hum Mutat 33:22–28.
82. Vega A, Campos B, Bressac-De-Paillerets B, Bond PM, Janin N, Douglas FS, Domenech M, Baena M, Pericay C, Alonso C, Carracedo A, Baiget M, et al. 2001. The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat 17:520–521.
83. 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.
84. 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, et al. 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.
85. Wappenschmidt B, Becker AA, Hauke J, Weber U, Engert S, Kohler J, Kast K, Arnold N, Rhiem K, Hahnen E, Meindl A, Schmutzler RK. 2012. Analysis of 30 putative BRCA1 splicing mutations in hereditary breast and ovarian cancer families identifies exonic splice site mutations that escape in silico prediction. PLoS One 7:e50800.
86. Whiley PJ, Pettigrew CA, Brewster BL, Walker LC, Spurdle AB, Brown MA. 2010. Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts. BMC Med Genet 11:80.
87. Whiley PJ, Guidugli L, Walker LC, Healey S, Thompson BA, Lakhani SR, Da Silva LM, Tavtigian SV, Goldgar DE, Brown MA, Couch FJ, Spurdle AB. 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.
88. Whiley PJ, de la Hoya M, Thomassen M, Becker A, Brandao R, Pedersen IS, Montagna M, Menendez M, Quiles F, Gutierrez-Enriquez S, De Leeneer K, Tenes A, et al. 2014a. Comparison of mRNA splicing assay protocols across multiple laboratories: recommendations for best practice in standardized clinical testing. Clin Chem 60:341–352.
89. Whiley PJ, Parsons MT, Leary J, Tucker K, Warwick L, Dopita B, Thorne H, Lakhani SR, Goldgar DE, Brown MA, Spurdle AB. 2014b. Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation. PLoS One 9:e86836.
90. Willems P, Magri V, Cretnik M, Fasano M, Jakubowska A, Levanat S, Lubinski J, Marras E, Musani V, Thierens H, Vandersickel V, Perletti G, Vral A. 2009. Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg). Int J Oncol 34:1005–1015.
91. Xu CF, Chambers JA, Nicolai H, Brown MA, Hujeirat Y, Mohammed S, Hodgson S, Kelsell DP, Spurr NK, Bishop DT, Solomon E. 1997. Mutations and alternative splicing of the BRCA1 gene in UK breast/ovarian cancer families. Genes Chromosomes Cancer 18:102–110.
92. Yang Z. 1998. Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol Biol Evol 15:568–573.
93. Yang Y, Swaminathan S, Martin BK, Sharan SK. 2003. Aberrant splicing induced by missense mutations in BRCA1: clues from a humanized mouse model. Hum Mol Genet 12:2121–2131.
94. Yeo G, Burge CB. 2004. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11:377–394.
95. Zhang L, Chen L, Bacares R, Ruggeri JM, Somar J, Kemel Y, Stadler ZK, Offit K. 2011. BRCA1 R71K missense mutation contributes to cancer predisposition by increasing alternative transcript levels. Breast Cancer Res Treat 130:1051–1056.