The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Mara Colombo, Irene Lòpez-Perolio, Huong D. Meeks, Laura Caleca, Michael T. Parsons, Hongyan Li, Giovanna De Vecchi, Emma Tudini, Claudia Foglia, Patrizia Mondini, Siranoush Manoukian, Raquel Behar, Encarna B.Gómez Garcia, Alfons Meindl, Marco Montagna, Dieter Niederacher, Ane Y. Schmidt, Liliana Varesco, Barbara Wappenschmidt, Manjeet K. BollaJoe Dennis, Kyriaki Michailidou, Qin Wang, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. Beckmann, Alicia Beeghly-Fadel, Javier Benitez, Bram Boeckx, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Hiltrud Brauch, Barbara Burwinkel, Jenny Chang-Claude, Don M. Conroy, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Montserrat García-Closas, Graham G. Giles, Anna González-Neira, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Mikael Hartman, Jan Hauke, Antoinette Hollestelle, John L. Hopper, Anna Jakubowska, Audrey Jung, Veli Matti Kosma, Diether Lambrechts, Loid Le Marchand, Annika Lindblom, Jan Lubinski, Arto Mannermaa, Sara Margolin, Hui Miao, Roger L. Milne, Susan L. Neuhausen, Heli Nevanlinna, Janet E. Olson, Paolo Peterlongo, Julian Peto, Katri Pylkäs, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Mee Hoong See, Anthony Swerdlow, Melissa C. Southey, Soo H. Teo, Amanda E. Toland, Ian Tomlinson, Thérèse Truong, Christi J. van Asperen, Ans M.W. van den Ouweland, Lizet E. van der Kolk, Robert Winqvist, Drakoulis Yannoukakos, Wei Zheng, kConFab/AOCS Investigators, Alison M. Dunning, Douglas F. Easton, Alex Henderson, Frans B.L. Hogervorst, Louise Izatt, Kenneth Offitt, Lucy E. Side, Elizabeth J. van Rensburg, EMBRACE Study, HEBON Study, Lesley McGuffog, Antonis C. Antoniou, Georgia Chenevix-Trench, Amanda B. Spurdle, David E. Goldgar, Miguel de la Hoya, Paolo Radice

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9 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)729-741
Number of pages13
JournalHuman Mutation
Issue number5
Publication statusPublished - 1 May 2018
Externally publishedYes


  • BRCA2
  • digital PCR
  • multifactorial likelihood analysis
  • quantitative real-time PCR
  • spliceogenic variants

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