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

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ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies.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

Description

Funder: Telethon Cyprus 33173233


Funder: NHMRC Investigator Fellowships APP177524

Keywords
Humans, Female, Virulence, BRCA1 Protein, BRCA2 Protein, Ovarian Neoplasms, Genetic Predisposition to Disease, Breast Neoplasms
Journal Title
Br J Cancer
Conference Name
Journal ISSN
0007-0920
1532-1827
Volume Title
128
Publisher
Springer Science and Business Media LLC
Sponsorship
National Cancer Institute (U19CA148537)
European Commission (223175)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
Cancer Research UK (20861)
Cancer Research UK (23382)
Cancer Research UK (A26886)
Cancer Research UK (A16563)
Cancer Research UK (A12014)
Cancer Research UK (A10118)