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, kConFab/AOCS Investigators, 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
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Аннотация
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.
Для цитирования: 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, kConFab/AOCS Investigators, 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. The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.. Human mutation. 2018. DOI: 10.1002/humu.23411.
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