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@ARTICLE{Dorling:179971,
      author       = {L. Dorling and S. Carvalho and J. Allen and M. T. Parsons
                      and C. Fortuno and A. González-Neira and S. M. Heijl and M.
                      A. Adank and T. U. Ahearn and I. L. Andrulis and P. Auvinen
                      and H. Becher and M. W. Beckmann and S. Behrens$^*$ and M.
                      Bermisheva and N. V. Bogdanova and S. E. Bojesen and M. K.
                      Bolla and M. Bremer and I. Briceno and N. J. Camp and A.
                      Campbell and J. E. Castelao and J. Chang-Claude$^*$ and S.
                      J. Chanock and G. Chenevix-Trench and J. M. Collée and K.
                      Czene and J. Dennis and T. Dörk and M. Eriksson and D. G.
                      Evans and P. A. Fasching and J. Figueroa and H. Flyger and
                      M. Gabrielson and M. Gago-Dominguez and M. García-Closas
                      and G. G. Giles and G. Glendon and P. Guénel and M.
                      Gündert and A. Hadjisavvas and E. Hahnen and P. Hall and U.
                      Hamann$^*$ and E. F. Harkness and M. Hartman and F. B. L.
                      Hogervorst and A. Hollestelle and R. Hoppe and A. Howell and
                      A. Jakubowska and A. Jung$^*$ and E. Khusnutdinova and S.-W.
                      Kim and Y.-D. Ko and V. N. Kristensen and I. M. M. Lakeman
                      and J. Li and A. Lindblom and M. A. Loizidou and A.
                      Lophatananon and J. Lubiński and C. Luccarini and M. J.
                      Madsen and A. Mannermaa and M. Manoochehri$^*$ and S.
                      Margolin and D. Mavroudis and R. L. Milne and N. A. Mohd
                      Taib and K. Muir and H. Nevanlinna and W. G. Newman and J.
                      C. Oosterwijk and S. K. Park and P. Peterlongo and P. Radice
                      and E. Saloustros and E. J. Sawyer and R. K. Schmutzler and
                      M. Shah and X. Sim and M. C. Southey and H. Surowy$^*$ and
                      M. Suvanto and I. Tomlinson and D. Torres and T. Truong and
                      C. J. van Asperen and R. Waltes and Q. Wang and X. R. Yang
                      and P. D. P. Pharoah and M. K. Schmidt and J. Benitez and B.
                      Vroling and A. M. Dunning and S. H. Teo and A. Kvist and M.
                      de la Hoya and P. Devilee and A. B. Spurdle and M. P. G.
                      Vreeswijk and D. F. Easton},
      collaboration = {NBCS Collaborators and k. Investigators and S.
                      Investigators},
      title        = {{B}reast cancer risks associated with missense variants in
                      breast cancer susceptibility genes.},
      journal      = {Genome medicine},
      volume       = {14},
      number       = {1},
      issn         = {1756-994X},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2022-01011},
      pages        = {51},
      year         = {2022},
      abstract     = {Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2,
                      and PALB2 are associated with increased breast cancer risk,
                      but risks associated with missense variants in these genes
                      are uncertain.We analyzed data on 59,639 breast cancer cases
                      and 53,165 controls from studies participating in the Breast
                      Cancer Association Consortium BRIDGES project. We sampled
                      training $(80\%)$ and validation $(20\%)$ sets to analyze
                      rare missense variants in ATM (1146 training variants),
                      BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We
                      evaluated breast cancer risks according to five in silico
                      prediction-of-deleteriousness algorithms, functional protein
                      domain, and frequency, using logistic regression models and
                      also mixture models in which a subset of variants was
                      assumed to be risk-associated.The most predictive in silico
                      algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD
                      (ATM). Increased risks appeared restricted to functional
                      protein domains for ATM (FAT and PIK domains) and BRCA1
                      (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data
                      were compatible with small subsets (approximately $7\%,$
                      $2\%,$ and $0.6\%,$ respectively) of rare missense variants
                      giving similar risk to those of protein truncating variants
                      in the same gene. For CHEK2, data were more consistent with
                      a large fraction (approximately $60\%)$ of rare missense
                      variants giving a lower risk (OR 1.75, $95\%$ CI
                      (1.47-2.08)) than CHEK2 protein truncating variants. There
                      was little evidence for an association with risk for
                      missense variants in PALB2. The best fitting models were
                      well calibrated in the validation set.These results will
                      inform risk prediction models and the selection of candidate
                      variants for functional assays and could contribute to the
                      clinical reporting of gene panel testing for breast cancer
                      susceptibility.},
      keywords     = {Breast cancer (Other) / Genetic epidemiology (Other) /
                      Missense variants (Other) / Risk prediction (Other)},
      cin          = {C020 / B072 / B070 / C080},
      ddc          = {610},
      cid          = {I:(DE-He78)C020-20160331 / I:(DE-He78)B072-20160331 /
                      I:(DE-He78)B070-20160331 / I:(DE-He78)C080-20160331},
      pnm          = {313 - Krebsrisikofaktoren und Prävention (POF4-313)},
      pid          = {G:(DE-HGF)POF4-313},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35585550},
      doi          = {10.1186/s13073-022-01052-8},
      url          = {https://inrepo02.dkfz.de/record/179971},
}