Daniela Turchetti

Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2

Background BRCA1/2 testing is crucial to guide clinical decisions in patients with hereditary breast/ovarian cancer, but detection of variants of uncertain significance (VUSs) prevents proper management of carriers. The ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) BRCA1/2 Variant Curation Expert Panel (VCEP) has recently developed BRCA1/2 variant classification guidelines consistent with ClinGen processes, specified against the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular-Pathology) classification framework. Methods The ClinGen-approved BRCA1/2-specified ACMG/AMP classification guidelines were applied to BRCA1/2 VUSs identified from 2011 to 2022 in a series of patients, retrieving information from the VCEP documentation, public databases, literature and ENIGMA unpublished data. Then, we critically re-evaluated carrier families based on new results and checked consistency of updated classification with main sources for clinical interpretation of BRCA1/2 variants. Results Among 166 VUSs detected in 231 index cases, 135 (81.3%) found in 197 index cases were classified by applying BRCA1/2-specified ACMG/AMP criteria: 128 (94.8%) as Benign/Likely Benign and 7 (5.2%) as Pathogenic/Likely Pathogenic. The average time from the first report as ‘VUS’ to classification using this approach was 49.4 months. Considering that 15 of these variants found in 64 families had already been internally reclassified prior to this work, this study provided 121 new reclassifications among the 151 (80.1%) remaining VUSs, relevant to 133/167 (79.6%) families. Conclusions These results demonstrated the effectiveness of new BRCA1/2 ACMG/AMP classification guidelines for VUS classification within a clinical cohort, and their important clinical impact. Furthermore, they suggested a cadence of no more than 3 years for regular review of VUSs, which however requires time, expertise and resources.

Intrafamilial communication of hereditary breast and ovarian cancer genetic information in Italian women: towards a personalised approach

Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/partner. Younger women, those living with their husband/partner, and those who described family communication as open/profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1-10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.