Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance

Nicholas T. Woods, Rebekah Baskin, Volha Golubeva, Ankita Jhuraney, Giuliana De-Gregoriis, Tereza Vaclova, David E. Goldgar, Fergus J. Couch, Marcelo Alex Carvalho, Edwin S. Iversen, Alvaro N.A. Monteiro

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


Variants of Uncertain Significance (VUS) are genetic variants whose association with a disease phenotype has not been established. They are a common finding in sequencing-based genetic tests and pose a significant clinical challenge. The objective of this study was to assess the use of functional data to classify variants according to pathogenicity. We conduct functional analysis of a large set of BRCA1 VUS combining a validated functional assay with VarCall, a Bayesian hierarchical model to estimate the likelihood of pathogenicity given the functional data. The results from the functional assays were incorporated into a joint analysis of 214 BRCA1 VUS to predict their likelihood of pathogenicity (breast cancer). We show that applying the VarCall model (1.0 sensitivity; lower bound of 95% confidence interval (CI) = 0.75 and 1.0 specificity; lower bound of 95% CI = 0.83) to the current set of BRCA1 variants, use of the functional data would significantly reduce the number of VUS associated with the C-Terminal region of the BRCA1 protein by ~ 87%. We extend this work developing yeast-based functional assays for two other genes coding for BRCT domain containing proteins, MCPH1 and MDC1. Analysis of missense variants in MCPH1 and MDC1 shows that structural inference based on the BRCA1 data set can aid in prioritising variants for further analysis. Taken together our results indicate that systematic functional assays can provide a robust tool to aid in clinical annotation of VUS. We propose that well-validated functional assays could be used for clinical annotation even in the absence of additional sources of evidence.

Original languageEnglish (US)
Article number16001
Journalnpj Genomic Medicine
StatePublished - Mar 2 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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