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Title: The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.
Colombo, Mara
Lòpez-Perolio, Irene
Meeks, Huong D
Caleca, Laura
Parsons, Michael T
Li, Hongyan
De Vecchi, Giovanna
Tudini, Emma
Foglia, Claudia
Mondini, Patrizia
Manoukian, Siranoush
Behar, Raquel
Garcia, Encarna B Gómez
Meindl, Alfons
Montagna, Marco
Niederacher, Dieter
Schmidt, Ane Y
Varesco, Liliana
Wappenschmidt, Barbara
Bolla, Manjeet K
Dennis, Joe
Michailidou, Kyriaki
Wang, Qin
Aittomäki, Kristiina
Andrulis, Irene L
Anton-Culver, Hoda
Arndt, Volker
Beckmann, Matthias W
Beeghly-Fadel, Alicia
Benitez, Javier
Boeckx, Bram
Bogdanova, Natalia V
Bojesen, Stig E
Bonanni, Bernardo
Brauch, Hiltrud
Brenner, Hermann
Burwinkel, Barbara
Chang-Claude, Jenny
Conroy, Don M
Couch, Fergus J
Cox, Angela
Cross, Simon S
Czene, Kamila
Devilee, Peter
Dörk, Thilo
Eriksson, Mikael
Fasching, Peter A
Figueroa, Jonine
Fletcher, Olivia
Flyger, Henrik
Gabrielson, Marike
García-Closas, Montserrat
Giles, Graham G
González-Neira, Anna
Guénel, Pascal
Haiman, Christopher A
Hall, Per
Hamann, Ute
Hartman, Mikael
Hauke, Jan
Hollestelle, Antoinette
Hopper, John L
Jakubowska, Anna
Jung, Audrey
Kosma, Veli-Matti
Lambrechts, Diether
Le Marchand, Loid
Lindblom, Annika
Lubinski, Jan
Mannermaa, Arto
Margolin, Sara
Miao, Hui
Milne, Roger L
Neuhausen, Susan L
Nevanlinna, Heli
Olson, Janet E
Peterlongo, Paolo
Peto, Julian
Pylkäs, Katri
Sawyer, Elinor J
Schmidt, Marjanka K
Schmutzler, Rita K
Schneeweiss, Andreas
Schoemaker, Minouk J
See, Mee Hoong
Southey, Melissa C
Swerdlow, Anthony
Teo, Soo H
Toland, Amanda E
Tomlinson, Ian
Truong, Thérèse
van Asperen, Christi J
van den Ouweland, Ans M W
van der Kolk, Lizet E
Winqvist, Robert
Yannoukakos, Drakoulis
Zheng, Wei
Dunning, Alison M
Easton, Douglas F
Henderson, Alex
Hogervorst, Frans B L
Izatt, Louise
Offitt, Kenneth
Side, Lucy E
van Rensburg, Elizabeth J
Embrace, Study
Hebon, Study
McGuffog, Lesley
Antoniou, Antonis C
Chenevix-Trench, Georgia
Spurdle, Amanda B
Goldgar, David E
Hoya, Miguel de la
Radice, Paolo
Issue Date: 2018
Citation: Hum. Mutat..2018 05;(39)5:729-741
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
PMID: 29460995
Rights: openAccess
Appears in Collections:Fundaciones e Institutos de Investigación > IIS H. U. Clínico San Carlos > Artículos

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