Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance

Paulo C.M. Lyra, Thales C. Nepomuceno, Marcele L.M. de Souza, Géssica F. Machado, Mariana F. Veloso, Taciane B. Henriques, Diandra Z. dos Santos, Iuly G. Ribeiro, Roberto S. Ribeiro, Leticia B.A. Rangel, Marcy Richardson, Edwin S. Iversen, David Goldgar, Fergus J. Couch, Marcelo A. Carvalho, Alvaro N.A. Monteiro

Research output: Contribution to journalArticlepeer-review


Purpose: BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification. Methods: We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (≥80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification. Results: Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach. Conclusion: High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

Original languageEnglish (US)
Pages (from-to)306-315
Number of pages10
JournalGenetics in Medicine
Issue number2
StatePublished - Feb 2021


  • ACMG/AMP guidelines
  • BRCA1
  • breast and ovarian cancer
  • functional assays
  • variants of uncertain significance

ASJC Scopus subject areas

  • Genetics(clinical)


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