. 2023 Jun;128(12):2283-2294.

doi: 10.1038/s41416-023-02263-5. Epub 2023 Apr 19.

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Denise G O'Mahony^{1

2}, Susan J Ramus^{3

4}, Melissa C Southey^{5

6

7}, Nicola S Meagher^{3

4

8}, Andreas Hadjisavvas², Esther M John^{9

10}, Ute Hamann¹¹, Evgeny N Imyanitov¹², Irene L Andrulis^{13

14}, Priyanka Sharma¹⁵, Mary B Daly¹⁶, Christopher R Hake¹⁷, Jeffrey N Weitzel¹⁸, Anna Jakubowska^{19

20}, Andrew K Godwin²¹, Adalgeir Arason^{22

23}, Anita Bane²⁴, Jacques Simard²⁵, Penny Soucy²⁵, Maria A Caligo²⁶, Phuong L Mai²⁷, Kathleen B M Claes²⁸, Manuel R Teixeira^{29

30}, Wendy K Chung³¹, Conxi Lazaro³², Peter J Hulick^{33

34}, Amanda E Toland³⁵, Inge Sokilde Pedersen^{36

37

38}; HEBON Investigators; Susan L Neuhausen³⁹, Ana Vega^{40

41

42}, Miguel de la Hoya⁴³, Heli Nevanlinna⁴⁴, Mallika Dhawan⁴⁵, Valentina Zampiga⁴⁶, Rita Danesi⁴⁷, Liliana Varesco⁴⁸, Viviana Gismondi⁴⁸, Valerio Gaetano Vellone⁴⁹, Paul A James⁵⁰, Ramunas Janavicius^{51

52}, Liene Nikitina-Zake⁵³, Finn Cilius Nielsen⁵⁴, Thomas van Overeem Hansen^{55

56}, Tanja Pejovic^{57

58}, Ake Borg⁵⁹, Johanna Rantala⁶⁰, Kenneth Offit^{61

62}, Marco Montagna⁶³, Katherine L Nathanson⁶⁴, Susan M Domchek⁶⁴, Ana Osorio^{65

66

67}, María J García⁶⁸, Beth Y Karlan⁶⁹; GEMO Study Collaborators; Anna De Fazio^{8

70

71

72}, David Bowtell^{73

74}; AOCS Group; Lesley McGuffog⁷⁵, Goska Leslie⁷⁵, Michael T Parsons⁷⁶, Thilo Dörk⁷⁷, Lisa-Marie Speith⁷⁷, Elizabeth Santana Dos Santos^{78

79

80}, Alexandre André B A da Costa^{80

81}, Paolo Radice⁸², Paolo Peterlongo⁸³, Laura Papi⁸⁴, Christoph Engel^{85

86}, Eric Hahnen^{87

88}, Rita K Schmutzler^{87

88

89}, Barbara Wappenschmidt^{87

88}, Douglas F Easton^{75

90}, Marc Tischkowitz^{91

92}, Christian F Singer⁹³, Yen Yen Tan⁹³, Alice S Whittemore^{9

94}, Weiva Sieh^{95

96}, James D Brenton⁹⁷, Drakoulis Yannoukakos⁹⁸, Florentia Fostira⁹⁸, Irene Konstantopoulou⁹⁸, Jana Soukupova⁹⁹, Michal Vocka¹⁰⁰; CZECANCA Consortium; Georgia Chenevix-Trench¹⁰¹, Paul D P Pharoah^{75

90}, Antonis C Antoniou⁷⁵, David E Goldgar¹⁰², Amanda B Spurdle⁷⁶, Kyriaki Michailidou^{103

104}; Consortium of Investigators of Modifiers of BRCA1/2; Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium

Collaborators, Affiliations

Collaborators

Marian J E Mourits, Fabienne Lesueur, Anna De Fazio, Miguel de la Hoya, Thomas van Overeem Hansen, Elizabeth Santana Dos Santos

Affiliations

¹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus.
² Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus.
³ School of Clinical Medicine, University of New South Wales Medicine and Health, University of New South Wales Sydney, Sydney, NSW, 2052, Australia.
⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia.
⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia.
⁶ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁷ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
⁸ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
⁹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹⁰ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
¹¹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
¹² N.N. Petrov Institute of Oncology, St. Petersburg, 197758, Russia.
¹³ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1×5, Canada.
¹⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁵ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA.
¹⁶ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
¹⁷ Waukesha Memorial Hospital-Pro Health Care, Waukesha, WI, 53188, USA.
¹⁸ The University of Kansas Cancer Center, Kansas City, MO, 66160, USA.
¹⁹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 171-252, Poland.
²⁰ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, 171-252, Poland.
²¹ Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
²² Department of Pathology, Landspitali University Hospital, Reykjavik, 101, Iceland.
²³ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
²⁴ Department of Pathology & Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, ON, L8V 1C3, Canada.
²⁵ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada.
²⁶ SOD Genetica Molecolare, University Hospital, Pisa, 56126, Italy.
²⁷ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
²⁸ Centre for Medical Genetics, Ghent University, Gent, 9000, Belgium.
²⁹ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Comprehensive Cancer Center, Porto, 4200-072, Portugal.
³⁰ School of Medicine and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, 4050-013, Portugal.
³¹ Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
³² Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, 08908, Spain.
³³ Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, 60201, USA.
³⁴ The University of Chicago Pritzker School of Medicine, Chicago, IL, 60637, USA.
³⁵ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA.
³⁶ Molecular Diagnostics, Aalborg University Hospital, Aalborg, 9000, Denmark.
³⁷ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, 9000, Denmark.
³⁸ Department of Clinical Medicine, Aalborg University, Aalborg, 9000, Denmark.
³⁹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
⁴⁰ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.
⁴¹ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, 15706, Spain.
⁴² Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, 15706, Spain.
⁴³ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, 28040, Spain.
⁴⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland.
⁴⁵ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, 94143-1714, USA.
⁴⁶ Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
⁴⁷ Romagna Cancer Registry, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, 47014, Italy.
⁴⁸ Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, 16132, Italy.
⁴⁹ Unit of Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, 16132, Italy.
⁵⁰ Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, 14049-900, Brazil.
⁵¹ Faculty of Medicine, Institute of Biomedical Sciences, Department of Human and Medical Genetics, Vilnius University, Vilnius, LT-03101, Lithuania.
⁵² State Research Institute Centre for Innovative Medicine, Vilnius, 8410, Lithuania.
⁵³ Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia.
⁵⁴ Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark.
⁵⁵ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark.
⁵⁶ Department of Clinical Medicine, Faculty of Health and Medical Sciences, , University of Copenhagen, Copenhagen, 2200, Denmark.
⁵⁷ Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, 97239, USA.
⁵⁸ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA.
⁵⁹ Department of Oncology, Lund University and Skåne University Hospital, Lund, 222 41, Sweden.
⁶⁰ Clinical Genetics, Karolinska Institutet, Stockholm, 171 76, Sweden.
⁶¹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶² Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶³ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, 35128, Italy.
⁶⁴ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19066, USA.
⁶⁵ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
⁶⁶ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, 28029, Spain.
⁶⁷ Genetics Service, Fundación Jiménez Díaz, Madrid, 28040, Spain.
⁶⁸ Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
⁶⁹ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁷⁰ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.
⁷¹ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, 2145, Australia.
⁷² The University of Sydney, Sydney, NSW, 2145, Australia.
⁷³ Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
⁷⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3000, Australia.
⁷⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁷⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
⁷⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, 30625, Germany.
⁷⁸ Service de Génétique, Institut Curie, Paris, 75005, France.
⁷⁹ Oncology Center, Hospital Sirio-Libanes, São Paulo, 01308-050, Brazil.
⁸⁰ Department of Clinical Oncology, A.C.Camargo Cancer Center, São Paulo, 1509900, Brazil.
⁸¹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 2215, USA.
⁸² Unit of Preventive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, 20133, Italy.
⁸³ Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, 20139, Italy.
⁸⁴ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, 27571, Italy.
⁸⁵ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, 04107, Germany.
⁸⁶ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, 04103, Germany.
⁸⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany.
⁸⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany.
⁸⁹ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50931, Germany.
⁹⁰ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
⁹¹ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, H4A 3J1, Canada.
⁹² Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁹³ Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, 1090, Austria.
⁹⁴ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁹⁵ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁹⁷ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
⁹⁸ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, 15310, Greece.
⁹⁹ Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12000, Czech Republic.
¹⁰⁰ Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12000, Czech Republic.
¹⁰¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
¹⁰² Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
¹⁰³ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus. kyriakimi@cing.ac.cy.
¹⁰⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. kyriakimi@cing.ac.cy.

PMID: 37076566
PMCID: PMC10241792
DOI: 10.1038/s41416-023-02263-5

Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

Denise G O'Mahony et al. Br J Cancer. 2023 Jun.

. 2023 Jun;128(12):2283-2294.

doi: 10.1038/s41416-023-02263-5. Epub 2023 Apr 19.

Authors

Collaborators

Marian J E Mourits, Fabienne Lesueur, Anna De Fazio, Miguel de la Hoya, Thomas van Overeem Hansen, Elizabeth Santana Dos Santos

Affiliations

¹ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus.
² Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus.
³ School of Clinical Medicine, University of New South Wales Medicine and Health, University of New South Wales Sydney, Sydney, NSW, 2052, Australia.
⁴ Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia.
⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia.
⁶ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
⁷ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
⁸ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia.
⁹ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA.
¹⁰ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA.
¹¹ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
¹² N.N. Petrov Institute of Oncology, St. Petersburg, 197758, Russia.
¹³ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1×5, Canada.
¹⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
¹⁵ Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA.
¹⁶ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
¹⁷ Waukesha Memorial Hospital-Pro Health Care, Waukesha, WI, 53188, USA.
¹⁸ The University of Kansas Cancer Center, Kansas City, MO, 66160, USA.
¹⁹ Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, 171-252, Poland.
²⁰ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, 171-252, Poland.
²¹ Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, 66160, USA.
²² Department of Pathology, Landspitali University Hospital, Reykjavik, 101, Iceland.
²³ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
²⁴ Department of Pathology & Molecular Medicine, Juravinski Hospital and Cancer Centre, McMaster University, Hamilton, ON, L8V 1C3, Canada.
²⁵ Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, G1V 4G2, Canada.
²⁶ SOD Genetica Molecolare, University Hospital, Pisa, 56126, Italy.
²⁷ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
²⁸ Centre for Medical Genetics, Ghent University, Gent, 9000, Belgium.
²⁹ Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO Porto)/Comprehensive Cancer Center, Porto, 4200-072, Portugal.
³⁰ School of Medicine and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, 4050-013, Portugal.
³¹ Departments of Pediatrics and Medicine, Columbia University, New York, NY, 10032, USA.
³² Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, 08908, Spain.
³³ Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, 60201, USA.
³⁴ The University of Chicago Pritzker School of Medicine, Chicago, IL, 60637, USA.
³⁵ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, 43210, USA.
³⁶ Molecular Diagnostics, Aalborg University Hospital, Aalborg, 9000, Denmark.
³⁷ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, 9000, Denmark.
³⁸ Department of Clinical Medicine, Aalborg University, Aalborg, 9000, Denmark.
³⁹ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
⁴⁰ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, 28029, Spain.
⁴¹ Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, 15706, Spain.
⁴² Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, 15706, Spain.
⁴³ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, 28040, Spain.
⁴⁴ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, 00290, Finland.
⁴⁵ Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, 94143-1714, USA.
⁴⁶ Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
⁴⁷ Romagna Cancer Registry, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, 47014, Italy.
⁴⁸ Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, 16132, Italy.
⁴⁹ Unit of Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, 16132, Italy.
⁵⁰ Department of Gynecology and Obstetrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, 14049-900, Brazil.
⁵¹ Faculty of Medicine, Institute of Biomedical Sciences, Department of Human and Medical Genetics, Vilnius University, Vilnius, LT-03101, Lithuania.
⁵² State Research Institute Centre for Innovative Medicine, Vilnius, 8410, Lithuania.
⁵³ Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia.
⁵⁴ Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark.
⁵⁵ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DK-2100, Denmark.
⁵⁶ Department of Clinical Medicine, Faculty of Health and Medical Sciences, , University of Copenhagen, Copenhagen, 2200, Denmark.
⁵⁷ Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, 97239, USA.
⁵⁸ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA.
⁵⁹ Department of Oncology, Lund University and Skåne University Hospital, Lund, 222 41, Sweden.
⁶⁰ Clinical Genetics, Karolinska Institutet, Stockholm, 171 76, Sweden.
⁶¹ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶² Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
⁶³ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, 35128, Italy.
⁶⁴ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, 19066, USA.
⁶⁵ Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
⁶⁶ Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, 28029, Spain.
⁶⁷ Genetics Service, Fundación Jiménez Díaz, Madrid, 28040, Spain.
⁶⁸ Computational Oncology Group, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain.
⁶⁹ David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
⁷⁰ Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.
⁷¹ Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, 2145, Australia.
⁷² The University of Sydney, Sydney, NSW, 2145, Australia.
⁷³ Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
⁷⁴ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, 3000, Australia.
⁷⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁷⁶ Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
⁷⁷ Gynaecology Research Unit, Hannover Medical School, Hannover, 30625, Germany.
⁷⁸ Service de Génétique, Institut Curie, Paris, 75005, France.
⁷⁹ Oncology Center, Hospital Sirio-Libanes, São Paulo, 01308-050, Brazil.
⁸⁰ Department of Clinical Oncology, A.C.Camargo Cancer Center, São Paulo, 1509900, Brazil.
⁸¹ Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, 2215, USA.
⁸² Unit of Preventive Medicine: Molecular Bases of Genetic Risk, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, 20133, Italy.
⁸³ Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, 20139, Italy.
⁸⁴ Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, 27571, Italy.
⁸⁵ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, 04107, Germany.
⁸⁶ LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, 04103, Germany.
⁸⁷ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany.
⁸⁸ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50937, Germany.
⁸⁹ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 50931, Germany.
⁹⁰ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
⁹¹ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, H4A 3J1, Canada.
⁹² Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, CB2 0QQ, UK.
⁹³ Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, 1090, Austria.
⁹⁴ Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁹⁵ Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁹⁷ Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
⁹⁸ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, 15310, Greece.
⁹⁹ Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12000, Czech Republic.
¹⁰⁰ Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, 12000, Czech Republic.
¹⁰¹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
¹⁰² Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
¹⁰³ Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus. kyriakimi@cing.ac.cy.
¹⁰⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. kyriakimi@cing.ac.cy.

PMID: 37076566
PMCID: PMC10241792
DOI: 10.1038/s41416-023-02263-5

Abstract

Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system.

Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong).

Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis.

Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Flowchart of study design and methods.**
Carriers refer to individuals with a reported germline pathogenic or likely pathogenic variant in *BRCA1* or *BRCA2*. Non-carriers refer to individuals tested negative for *BRCA1* and/or *BRCA2* in germline. The ‘other’ category comprised rare forms of ovarian cancer not belonging to any of the other subtypes, including tumours defined as: ‘other’ by data sources not specifying tumour histology; mixed-epithelial carcinomas; carcinosarcomas, transitional cell (Brenner tumours), undifferentiated or poorly differentiated; squamous cell. HGSC high-grade serous carcinoma, LGSC low-grade serous carcinoma.

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Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

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Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

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