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Original research
Clinical implications of VUS reclassification in a single-centre series from application of ACMG/AMP classification rules specified for BRCA1/2
  1. Giovanni Innella1,2,
  2. Simona Ferrari2,
  3. Sara Miccoli2,
  4. Elena Luppi1,2,
  5. Cristina Fortuno3,
  6. Michael T Parsons3,
  7. Amanda B Spurdle3,
  8. Daniela Turchetti1,2
  1. 1 Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
  2. 2 IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
  3. 3 Population Health, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
  1. Correspondence to Dr Giovanni Innella, Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy, Bologna, Italy; giovanni.innella2{at}unibo.it

Abstract

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in a series of patients, retrieving information from the VCEP documentation, public databases, literature and ENIGMA unpublished data.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.

  • Genetic Counseling

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study.

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Footnotes

  • Contributors Conceptualisation: ABS, GI and DT; methodology: ABS, MTP and CF; investigation and data curation: GI, SF, SM and EL; writing—original draft preparation: GI; writing—review and editing: ABS and DT; guarantor for the overall content: DT; all authors have read and agreed to the published version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.