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

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  • AOCS Group
  • CZECANCA Consortium
  • The Consortium of Investigators of Modifiers of BRCA1/2
  • Evidence-based Network for the Interpretation of Germline Mutant Alleles Consortium
  • HEBON Investigators
  • GEMO Study Collaborators

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ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.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.

OriginalsprogEngelsk
TidsskriftBritish Journal of Cancer
Vol/bind128
Udgave nummer12
Sider (fra-til)2283-2294
Antal sider12
ISSN0007-0920
DOI
StatusUdgivet - 2023

Bibliografisk note

Publisher Copyright:
© 2023, The Author(s).

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