title: In silico, in vitro and case-control analyses as an effective combination for analyzing BRCA1 and BRCA2 unclassified variants in a population-based sample.
abstract: Ascertaining the clinical consequences of BRCA1 and BRCA2 variants of uncertain significance (VUS) is currently indispensable for providing effective genetic counseling and preventive actions for families with hereditary breast and ovarian cancer (HBOC). To this end, we conducted a combination of in silico prediction and cDNA splicing analyses of 13 BRCA1 and 10 BRCA2 VUS identified in our cohort as well as a case-control analysis in a population-based sample of 10 recurrent VUS. We observed consistent results between the in silico predictions and sequencing analyses for all analyzed VUS. An abnormal cDNA pattern was observed for variants c.212+1G>A and c.5278-1G>A in BRCA1 and c.516+2T>A and c.8168A>G in BRCA2 according to in silico splicing prediction. A case-control study of VUS confirmed the polymorphisms of the c.67+62A>G, c.7008-62A>G and c.8851G>A BRCA2 variants previously published. c.4068G>A in the BRCA2 gene can also be considered a polymorphism due to its occurrence at a frequency greater than 1% in our population. Our study shows that employing population-based analysis and a combination of several in silico methods yields highly accurate information, resulting in a reliable tool for selecting variants for cDNA sequencing analysis in routine cancer genetic counseling units.
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Rodríguez-Balada
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain.
authors.forename: Bàrbara
authors.initials: B
authors.lastname: Roig
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, C/Sant Llorenç, Reus, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Martorell
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Melé
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Salvat
authors.affiliation: Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, C/Sant Llorenç, Reus, Spain.
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Borràs
authors.affiliation: Cancer Genetic Counseling Unit (Oncology Research Group), Institut d'Oncologia de la Catalunya Sud (IOCS), Hospital Universitari Sant Joan de Reus, IISPV, Universitat Rovira i Virgili, Av. Del Dr. Josep Laporte, Reus, Spain. Electronic address: jguma@grupsagessa.com.
authors.forename: Josep
authors.initials: J
authors.lastname: Gumà
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D004252:DNA Mutational Analysis / Q000379:methods*; D018076:DNA, Complementary / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D005817:Genetic Counseling; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018076:DNA, Complementary
keywords: BRCA1; BRCA2; cDNA; cancer genetic counseling; splicing; variants of unknown significance