{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:37:34Z","timestamp":1791250654102,"version":"4.1.0"},"reference-count":36,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2012,7,13]]},"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes\n                      <jats:italic>BRCA1<\/jats:italic>\n                      and\n                      <jats:italic>BRCA2<\/jats:italic>\n                      is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G&gt;A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Measures of genetic risk (report of family history, segregation) were assessed for 68\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5096G&gt;A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5095C&gt;T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no\n                      <jats:italic>BRCA1<\/jats:italic>\n                      pathogenic mutation (BRCA-X).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comparison of\n                      <jats:italic>BRCA1<\/jats:italic>\n                      carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5096G&gt;A p.Arg1699Gln variant carriers had family histories that were less \u2018\n                      <jats:italic>BRCA1<\/jats:italic>\n                      -like\u2019 than\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5095C&gt;T p.Arg1699Trp mutation carriers (p&lt;0.00001), but more \u2018\n                      <jats:italic>BRCA1<\/jats:italic>\n                      -like\u2019 than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5096G\u2009&gt;A p.Arg1699Gln had reduced penetrance compared with the average truncating\n                      <jats:italic>BRCA1<\/jats:italic>\n                      mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results provide substantial evidence that the\n                      <jats:italic>BRCA1<\/jats:italic>\n                      c.5096G&gt;A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-101037","type":"journal-article","created":{"date-parts":[[2012,8,13]],"date-time":"2012-08-13T03:22:47Z","timestamp":1344828167000},"page":"525-532","source":"Crossref","is-referenced-by-count":125,"title":["BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk"],"prefix":"10.1136","volume":"49","author":[{"given":"Amanda B","family":"Spurdle","sequence":"first","affiliation":[{"name":"1Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia"},{"name":"2School of Medicine, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip J","family":"Whiley","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryony","family":"Thompson","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia"},{"name":"2School of Medicine, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingjian","family":"Feng","sequence":"additional","affiliation":[{"name":"3Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Healey","sequence":"additional","affiliation":[{"name":"1Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A","family":"Brown","sequence":"additional","affiliation":[{"name":"4School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Pettigrew","sequence":"additional","affiliation":[{"name":"4School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"kConFab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christi J","family":"Van Asperen","sequence":"additional","affiliation":[{"name":"6Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margreet G E M","family":"Ausems","sequence":"additional","affiliation":[{"name":"7Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna A","family":"Kattentidt-Mouravieva","sequence":"additional","affiliation":[{"name":"8Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ans M W","family":"van den Ouweland","sequence":"additional","affiliation":[{"name":"8Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dutch","family":"Belgium UV Consortium","sequence":"additional","affiliation":[{"name":"9See Appendix for full list of ENIGMA collaborators contributing to this study, operating within and outside of country consortia"},{"name":"10Dutch Belgium UV Consortium, Co-ordinator F.B. Hogervorst, The Netherlands Cancer Institute, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Lindblom","sequence":"additional","affiliation":[{"name":"11Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maritta H","family":"Pigg","sequence":"additional","affiliation":[{"name":"12Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita K","family":"Schmutzler","sequence":"additional","affiliation":[{"name":"13Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Engel","sequence":"additional","affiliation":[{"name":"14Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfons","family":"Meindl","sequence":"additional","affiliation":[{"name":"15Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"German Consortium of Hereditary Breast and Ovarian Cancer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Caputo","sequence":"additional","affiliation":[{"name":"16Institut Curie, H\u00f4pital Ren\u00e9 Huguenin, Service d'Oncog\u00e9n\u00e9tique, U735 INSERM, Saint-Cloud, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga M","family":"Sinilnikova","sequence":"additional","affiliation":[{"name":"17Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon\/Centre Leon Berard, Lyon, France"},{"name":"18INSERM U1052, CNRS UMR5286, Universit\u00e9 Lyon 1, Centre de Recherche en Canc\u00e9rologie de Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosette","family":"Lidereau","sequence":"additional","affiliation":[{"name":"16Institut Curie, H\u00f4pital Ren\u00e9 Huguenin, Service d'Oncog\u00e9n\u00e9tique, U735 INSERM, Saint-Cloud, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"French COVAR group collaborators","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergus J","family":"Couch","sequence":"additional","affiliation":[{"name":"20Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Guidugli","sequence":"additional","affiliation":[{"name":"20Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas van Overeem","family":"Hansen","sequence":"additional","affiliation":[{"name":"21Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mads","family":"Thomassen","sequence":"additional","affiliation":[{"name":"22Department of Clinical Genetics, Odense University Hospital, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana M","family":"Eccles","sequence":"additional","affiliation":[{"name":"23Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Tucker","sequence":"additional","affiliation":[{"name":"24Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Benitez","sequence":"additional","affiliation":[{"name":"25Spanish National Cancer Centre, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Domchek","sequence":"additional","affiliation":[{"name":"26Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda E","family":"Toland","sequence":"additional","affiliation":[{"name":"27Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, 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