Article open access publication

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

Human Mutation, Wiley, ISSN 1098-1004

Volume 39, 5, 2018

DOI:10.1002/humu.23411, Dimensions: pub.1101126111, PMC: PMC5947288, PMID: 29460995,

Authors

Wang, Qin (12)
Andrulis, Irene L. (15) (16)
Benitez, Javier (21) (22)
Boeckx, Bram (23) (24)
Bojesen, Stig E. (27) (28) (29)
Brauch, Hiltrud (18) (31) (32)
Burwinkel, Barbara (18) (33)
Fasching, Peter A. (19) (39)
Figueroa, Jonine (40) (41)
Giles, Graham G (44) (45)
Hall, Per (37)
Hartman, Mikael (48) (49)
Hauke, Jan (11) (50)
Kosma, Veli-Matti (53) (54)
Mannermaa, Arto (53) (54)
Miao, Hui (49)
Milne, Roger L. (44) (45)
Pylkäs, Katri (60) (61)
Teo, Soo H. (65) (66)
Winqvist, Robert (60) (61)
Zheng, Wei (20)

Affiliations

Organisations

  1. (1) Fondazione IRCCS Istituto Nazionale dei Tumori, grid.417893.0
  2. (2) Hospital Clínico San Carlos, grid.411068.a
  3. (3) University of Utah Health Care, grid.412722.0
  4. (4) QIMR Berghofer Medical Research Institute, grid.1049.c
  5. (5) Maastricht University Medical Centre, grid.412966.e
  6. (6) Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany
  7. (7) Istituto Oncologico Veneto, grid.419546.b
  8. (8) Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich‐Heine University, Duesseldorf, Germany
  9. (9) Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  10. (10) Ospedale San Martino, grid.410345.7
  11. (11) University Hospital Cologne, grid.411097.a
  12. (12) University of Cambridge, grid.5335.0
  13. (13) Cyprus Institute of Neurology and Genetics, grid.417705.0
  14. (14) Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  15. (15) Mount Sinai Hospital, grid.416166.2
  16. (16) University of Toronto, grid.17063.33
  17. (17) University of California, Irvine, grid.266093.8
  18. (18) German Cancer Research Center, grid.7497.d
  19. (19) Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  20. (20) Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
  21. (21) Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  22. (22) Spanish National Cancer Research Centre, grid.7719.8
  23. (23) Flanders Institute for Biotechnology, grid.11486.3a
  24. (24) KU Leuven, grid.5596.f
  25. (25) N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
  26. (26) Hannover Medical School, grid.10423.34
  27. (27) Copenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  28. (28) Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  29. (29) University of Copenhagen, grid.5254.6, KU
  30. (30) European Institute of Oncology, grid.15667.33
  31. (31) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, grid.502798.1
  32. (32) University of Tübingen, grid.10392.39
  33. (33) Heidelberg University, grid.7700.0
  34. (34) University Cancer Center Hamburg, grid.412315.0
  35. (35) Mayo Clinic, grid.66875.3a
  36. (36) University of Sheffield, grid.11835.3e
  37. (37) Karolinska Institute, grid.4714.6
  38. (38) Leiden University Medical Center, grid.10419.3d
  39. (39) University of California, Los Angeles, grid.19006.3e
  40. (40) University of Edinburgh, grid.4305.2
  41. (41) National Cancer Institute, grid.48336.3a
  42. (42) Institute of Cancer Research, grid.18886.3f
  43. (43) Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark
  44. (44) University of Melbourne, grid.1008.9
  45. (45) Cancer Council Victoria, grid.3263.4
  46. (46) Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France
  47. (47) University of Southern California, grid.42505.36
  48. (48) National University Health System, grid.410759.e
  49. (49) National University of Singapore, grid.4280.e
  50. (50) University of Cologne, grid.6190.e
  51. (51) Erasmus University Medical Center, grid.5645.2
  52. (52) Pomeranian Medical University, grid.107950.a
  53. (53) Kuopio University Hospital, grid.410705.7
  54. (54) University of Eastern Finland, grid.9668.1
  55. (55) University of Hawaii at Manoa, grid.410445.0
  56. (56) City Of Hope National Medical Center, grid.410425.6
  57. (57) Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  58. (58) IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy
  59. (59) London School of Hygiene & Tropical Medicine, grid.8991.9
  60. (60) Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland
  61. (61) University of Oulu, grid.10858.34
  62. (62) King's College London, grid.13097.3c
  63. (63) Antoni van Leeuwenhoek Hospital, grid.430814.a
  64. (64) National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
  65. (65) University Malaya Medical Centre, grid.413018.f
  66. (66) Cancer Research Malaysia, grid.507182.9
  67. (67) The Ohio State University, grid.261331.4
  68. (68) University of Oxford, grid.4991.5
  69. (69) National Centre of Scientific Research Demokritos, grid.6083.d
  70. (70) Peter MacCallum Cancer Centre, grid.1055.1
  71. (71) Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
  72. (72) Guy's and St Thomas' NHS Foundation Trust, grid.420545.2
  73. (73) Memorial Sloan Kettering Cancer Center, grid.51462.34
  74. (74) Princess Anne Hospital, grid.415216.5
  75. (75) University of Pretoria, grid.49697.35

Description

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.

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University of Copenhagen

Danish Open Access Indicator

2018: Realized

Research area: Medicine

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2018: Level 2

Research area: Medicine

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Times Cited: 8

Field Citation Ratio (FCR): 5.03

Relative Citation ratio (RCR): 1.03

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