TY - JOUR
T1 - Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance
AU - Lyra, Paulo C.M.
AU - Nepomuceno, Thales C.
AU - de Souza, Marcele L.M.
AU - Machado, Géssica F.
AU - Veloso, Mariana F.
AU - Henriques, Taciane B.
AU - dos Santos, Diandra Z.
AU - Ribeiro, Iuly G.
AU - Ribeiro, Roberto S.
AU - Rangel, Leticia B.A.
AU - Richardson, Marcy
AU - Iversen, Edwin S.
AU - Goldgar, David
AU - Couch, Fergus J.
AU - Carvalho, Marcelo A.
AU - Monteiro, Alvaro N.A.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - ACMG/AMP guidelines
KW - BRCA1
KW - breast and ovarian cancer
KW - functional assays
KW - variants of uncertain significance
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U2 - 10.1038/s41436-020-00991-0
DO - 10.1038/s41436-020-00991-0
M3 - Article
C2 - 33087888
AN - SCOPUS:85092924565
SN - 1098-3600
VL - 23
SP - 306
EP - 315
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 2
ER -