Contribution of bioinformatics predictions and functional splicing assays to the interpretation of unclassified variants of the BRCA genes

European Journal of Human Genetics

Volumn 19, Issue 10, 2011, Pages 1052-1058

  Théry, Jean Christophe ^a   Krieger, Sophie ^b   Gaildrat, Pascaline ^a   Révillion, Françoise ^c   Buisine, Marie Pierre ^a   Killian, Audrey ^a   Duponchel, Christiane ^a   Rousselin, Antoine ^b   Vaur, Dominique ^b   Peyrat, Jean Philippe ^c   Berthet, Pascaline ^b   Frébourg, Thierry ^a   Martins, Alexandra ^a   Hardouin, Agnès ^b   Tosi, Mario ^a  

^a ROUEN UNIVERSITY HOSPITAL   (France)

^b CENTRE FRANÇOIS BACLESSE   (France)

^c CENTRE OSCAR LAMBRET   (France)

Author keywords

BRCA1 and BRCA2; breast and ovarian cancer; splicing defects; splicing reporter minigene; variants of unknown significance

Indexed keywords

BRCA1 PROTEIN; BRCA2 PROTEIN;

ARTICLE; BIOINFORMATICS; DNA DETERMINATION; DNA SPLICING; EXON; GENETIC VARIABILITY; HUMAN; NUCLEOTIDE SEQUENCE; ONCOGENE; PREDICTION; PRIORITY JOURNAL;

BRCA1 PROTEIN; BRCA2 PROTEIN; BREAST NEOPLASMS; COMPUTATIONAL BIOLOGY; FEMALE; GENES, BRCA1; GENES, BRCA2; GENES, REPORTER; GENETIC VARIATION; HUMANS; OVARIAN NEOPLASMS; PREDICTIVE VALUE OF TESTS; RNA SPLICE SITES; RNA SPLICING; RNA, MESSENGER;

EID: 80053052971     PISSN: 10184813     EISSN: 14765438     Source Type: Journal    
DOI: 10.1038/ejhg.2011.100     Document Type: Article

References (28)

1. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-ofconcept trial. Lancet 2010; 376: 235-244.
2. Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 2010; 107: 12629-12633.
3. Stalder L, Mü hlemann O: The meaning of nonsense. Trends Cell Biol 2008; 18: 315-321.
4. Gaildrat P, Killian A, Martins A, Tournier I, Frébourg T, Tosi M: Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants. Methods Mol Biol 2010; 653: 249-257.
5. Baralle D, Baralle M: Splicing in action: assessing disease causing sequence changes. J Med Genet 2005; 42: 737-748. (Pubitemid 41475248)
6. Tournier I, Vezain M, Martins A, et al. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat 2008; 29: 1412-1424. (Pubitemid 352774895)
7. Bonnet C, Krieger S, Vezain M, et al. 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 2008; 45: 438-446. (Pubitemid 351977134)
8. Vreeswijk MP, Kraan JN, van der Klift HM, et al. Intronic variants in BRCA1 and BRCA2 that affect RNA splicing can be reliably selected by splice-site prediction programs. Hum Mutat 2009; 30: 107-114.
9. Houdayer C, Dehainault C, Mattler C, et al. Evaluation of in silico splice tools for decision-making in molecular diagnosis. Hum Mutat 2008; 29: 975-982. (Pubitemid 351951292)
10. Zampieri S, Buratti E, Dominissini S, et al. Splicing mutations in glycogen-storage disease type II: evaluation of the full spectrum of mutations and their relation to patients phenotypes. Eur J Hum Genet 2011; 19: 422-431.
11. Hogervorst FB, Nederlof PM, Gille JJ, et al. Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method. Cancer Res 2003; 63: 1449-1453. (Pubitemid 36373627)
12. Casilli F, Tournier I, Sinilnikova OM, et al. The contribution of germline rearrangements to the spectrum of BRCA2 mutations. J Med Genet 2006; 43: e49.
13. Gaildrat P, Krieger S, Théry JC, et al. The BRCA1 c.5434C-G (p.Pro1812Ala) variant induces a deleterious exon 23 skipping by affecting exonic splicing regulatory elements. J Med Genet 2010; 47: 398-403.
14. Anczuków O, Buisson M, Salles MJ, et al. Unclassified variants identified in BRCA1 exon 11: consequences on splicing. Genes Chromosomes Cancer 2008; 47: 418-426. (Pubitemid 351451796)
15. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 2007; 81: 873-883. (Pubitemid 47580242)
16. Goldgar DE, Easton DF, Byrnes GB, et al. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 2008; 29: 1265-1272.
17. Whiley P, Guidugli L, Walker L, et al. 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 2011; 32: 678-687.
18. Chen X, Truong TT, Weaver J, et al. Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Hum Mutat 2006; 27: 427-435. (Pubitemid 43673329)
19. Claes K, Vandesompele J, Poppe B, et al. 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 2002; 21: 4171-4175. (Pubitemid 34712885)
20. Sanz DJ, Acedo A, Infante M, et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res 2010; 16: 1957-1967.
21. Walker LC, Whiley PJ, Couch FJ, et al. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat 2010; 31: E1484-E1505.
22. Karchin R, Agarwal M, Sali A, Couch F, Beattie MS: Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Inform 2008; 6: 203-216.
23. Dosil V, Tosar A, Cañadas C, et al. Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C4T as a case study. Clin Chem 2010; 56: 53-61.
24. Homolova K, Zavadakova P, Doktor TK, Schroeder LD, Kozich V, Andresen BS: The deep intronic c.903+469T4C 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 2010; 31: 437-444.
25. Farrugia DJ, Agarwal MK, Pankratz VS, et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res 2008; 68: 3523-3531.
26. Tavtigian SV, Deffenbaugh AM, Yin L, et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 2006; 43: 295-305.
27. Drikos I, Nounesis G, Vorgias CE: Characterization of cancer-linked BRCA1-BRCT missense variants and their interaction with phosphoprotein targets. Proteins 2009; 77: 464-476.
28. Hadjisavvas A, Charalambous E, Adamou A, Christodoulou CG, Kyriacou K: BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer. Hum Mutat 2003; 21: 171.