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Organization: Consortium of Investigators of Modifiers of BRCA1/2

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Article

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

O'Mahony, Denise G
Author O'Mahony, Denise G ORCID Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus
Ramus, Susan J
Author Ramus, Susan J ORCID School of Clinical Medicine, University of New South Wales Medicine and Health, University of New South Wales Sydney, Sydney, NSW, 2052, Australia Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia
Southey, Melissa C
Author Southey, Melissa C Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia
Meagher, Nicola S
Author Meagher, Nicola S ORCID School of Clinical Medicine, University of New South Wales Medicine and Health, University of New South Wales Sydney, Sydney, NSW, 2052, Australia Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales Sydney, Sydney, NSW, 2052, Australia The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, NSW, Australia
Hadjisavvas, Andreas
Author Hadjisavvas, Andreas Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, 2371, Cyprus
John, Esther M
Author John, Esther M Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, 94305, USA Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94304, USA
Hamann, Ute
Author Hamann, Ute Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany
Imyanitov, Evgeny N
Author Imyanitov, Evgeny N N.N. Petrov Institute of Oncology, St. Petersburg, 197758, Russia
Andrulis, Irene L
Author Andrulis, Irene L ORCID Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1×5, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada
Sharma, Priyanka
Author Sharma, Priyanka Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, 66205, USA

British journal of cancer. 2023 Jun ; 128 (12) : 2283-2294. [epub] 20230419

Br J Cancer
ISSN 1532-1827 | 0007-0920
Source

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.

MeSH
Genetic Predisposition to Disease MeSH
Humans MeSH
Breast Neoplasms * MeSH
Ovarian Neoplasms * genetics MeSH
BRCA1 Protein genetics MeSH
BRCA2 Protein genetics MeSH
Virulence MeSH
Check Tag
Humans MeSH
Female MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Research Support, N.I.H., Extramural MeSH
Research Support, U.S. Gov't, Non-P.H.S. MeSH
Names of Substances
BRCA1 protein, human MeSH Browser
BRCA2 protein, human MeSH Browser
BRCA1 Protein MeSH
BRCA2 Protein MeSH

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