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

M. Colombo, I. Lòpez-Perolio, H.D. Meeks, L. Caleca, M.T. Parsons, H. Li, G. De Vecchi, E. Tudini, C. Foglia, P. Mondini, S. Manoukian, R. Behar, E.B.G. Garcia, A. Meindl, M. Montagna, D. Niederacher, A.Y. Schmidt, L. Varesco, B. Wappenschmidt, M.K. BollaJ. Dennis, K. Michailidou, Q. Wang, K. Aittomäki, I.L. Andrulis, H. Anton-Culver, V. Arndt, M.W. Beckmann, A. Beeghly-Fadel, J. Benitez, B. Boeckx, N.V. Bogdanova, S.E. Bojesen, B. Bonanni, H. Brauch, H. Brenner, B. Burwinkel, J. Chang-Claude, D.M. Conroy, F.J. Couch, A. Cox, S.S. Cross, K. Czene, P. Devilee, T. Dörk, M. Eriksson, P.A. Fasching, J. Figueroa, O. Fletcher, H. Flyger, M. Gabrielson, M. García-Closas, G.G. Giles, A. González-Neira, P. Guénel, C.A. Haiman, P. Hall, U. Hamann, M. Hartman, J. Hauke, A. Hollestelle, J.L. Hopper, A. Jakubowska, A. Jung, V.-M. Kosma, D. Lambrechts, L. Le Marchand, A. Lindblom, J. Lubinski, A. Mannermaa, S. Margolin, H. Miao, R.L. Milne, S.L. Neuhausen, H. Nevanlinna, J.E. Olson, P. Peterlongo, J. Peto, K. Pylkäs, E.J. Sawyer, M.K. Schmidt, R.K. Schmutzler, A. Schneeweiss, M.J. Schoemaker, M.H. See, M.C. Southey, A. Swerdlow, S.H. Teo, A.E. Toland, I. Tomlinson, T. Truong, C.J. van Asperen, A.M.W. van den Ouweland, L.E. van der Kolk, R. Winqvist, D. Yannoukakos, W. Zheng, A.M. Dunning, D.F. Easton, A. Henderson, F.B.L. Hogervorst, L. Izatt, K. Offitt, L.E. Side, E.J. van Rensburg, S. Embrace, S. Hebon, L. McGuffog, A.C. Antoniou, G. Chenevix-Trench, A.B. Spurdle, D.E. Goldgar, M.D.L. Hoya, P. Radice, kConFab/AOCS Investigators

Research output: Contribution to journalArticlepeer-review


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. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)729-741
Number of pages13
JournalHuman Mutation
Issue number5
Publication statusPublished - 2018


  • BRCA2
  • digital PCR
  • multifactorial likelihood analysis
  • quantitative real-time PCR
  • spliceogenic variants
  • BRCA1 protein
  • BRCA2 protein
  • complementary DNA
  • isoprotein
  • messenger RNA
  • mitomycin
  • Article
  • breast cancer
  • cancer inhibition
  • cancer risk
  • case control study
  • causality
  • cell viability
  • controlled study
  • droplet digital polymerase chain reaction
  • exon
  • female
  • gene frequency
  • gene mutation
  • genetic analysis
  • genetic risk
  • genetic screening
  • genetic transcription
  • genetic variation
  • heterozygosity
  • heterozygote
  • human
  • human cell
  • lymphoblastoid cell line
  • major clinical study
  • multicenter study
  • percentage of viable cells
  • priority journal
  • protein function
  • qualitative analysis
  • quantitative analysis
  • real time polymerase chain reaction
  • segregation analysis
  • spliceosome


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