No. 366-Gynaecologic Management of Hereditary Breast and Ovarian Cancer.

OBJECTIVE: This Committee Opinion outlines the gynaecologic management recommendations for women diagnosed with hereditary breast and ovarian cancer syndrome (HBOC) with respect to screening, contraception, chemoprophylaxis, fertility considerations, risk-reducing surgery, and post-oophorectomy care. INTENDED USERS: This Committee Opinion is designed for gynaecologic oncologists, general gynaecologists, family physicians, genetic counsellors, registered nurses, nurse practitioners, residents, and health care providers. TARGET POPULATION: Adult women (18 years and older) with a pathogenic germline variant in the BRCA1, BRCA2, and other ovarian cancer-associated genes. EVIDENCE: While reviewing evidence, databases searched include Medline, Cochrane, and PubMed. Medical Subject Heading search terms used include BRCA AND gynaecology management, hormone replacement therapy, risk reduction, chemoprophylaxis, fertility from 01/2010 and 10/2017. Literature search was begun 07/2017 and finalized 10/2017. In total 183 studies were identified, and 101 were used. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the principal authors. The Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology framework (Table 1). The interpretation of strong and conditional (weak) recommendations is described in Table 2. The Summary of Findings is available upon request. BENEFITS, HARMS, AND COSTS: We may expect a risk reduction of up to 90% in women predisposed to HBOC who undergo risk-reducing bilateral salpingo-oophorectomy. The harms of iatrogenic premature menopause are offset by the benefits of risk reduction. By minimizing potential tubal/ovarian/peritoneal cancers, we can expect savings to the health care system. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the opinion should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Obstetricians and Gynaecologists of Canada.

Refinement of the assignment to the ACMG/AMP BS3 and PS3 criteria of eight BRCA1 variants of uncertain significance by integrating available functional data with protein interaction assays.

The clinical screening of cancer predisposition genes has led to the identification of a large number of variants of uncertain significance (VUS). Multifactorial likelihood models that predict the odds ratio for VUS in favor or against cancer causality, have been developed, but their use is limited by the amount of necessary data, which are difficult to obtain for rare variants. The guidelines for variant interpretation of the American College of Medical Genetics and Genomics along with the Association for Molecular Pathology (ACMG/AMP) state that "well-established" functional studies provide strong support of a pathogenic or benign impact (criteria PS3 and BS3, respectively) and can be used as evidence type to reach a final classification. Moreover, the Clinical Genome Resource Sequence Variant Interpretation Working Group developed rule specifications to refine the PS3/BS3 criteria. Recently, Lira PC et al. developed the "Hi Set" approach that generated PS3/BS3 codes for over two-thousands BRCA1 VUS. While highly successful, this approach did not discriminate a group of variants with conflicting evidences. Here, we aimed to implement the outcomes of the "Hi-set" approach applying Green Fluorescent Protein (GFP)-reassembly assays, assessing the effect of variants in the RING and BRCT domains of BRCA1 on the binding of these domains with the UbcH5a or ABRAXAS proteins, respectively. The analyses of 26 clinically classified variants, including 13 tested in our previous study, showed 100% sensitivity and specificity in identifying pathogenic and benign variants for both the RING/UbcH5a and the BRCTs/ABRAXAS interactions. We derived the strength of evidences generated by the GFP-reassembly assays corresponding to moderate for both PS3 and BS3 criteria assessment. The GFP-reassembly assays were applied to the functional characterization of 8 discordant variants from the study by Lyra et al. The outcomes of these analyses, combined with those reported in the "Hi Set" study, allowed the assignment of ACMG/AMP criteria in favor or against pathogenicity for all 8 examined variants. The above findings were validated with a semi-quantitative Mammalian Two-Hybrid approach, and totally concordant results were observed. Our data contributes in shedding light on the functional significance of BRCA1 VUS and on their clinical interpretation within the ACMG/AMP framework.