title: No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.
abstract: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
  
  
  
  We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
  
  
  
  The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
  
  
  
  These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
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authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Campbell
authors.affiliation: Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.affiliation: Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA Cancer Control and Population Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA.
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.affiliation: Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020365:RNA Helicases / Q000235:genetics*; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases
keywords: Cancer: breast