Driven by massively parallel sequencing and allied technologies, the scale of genetic predisposition testing is on a dramatic uptrend. While many patients are found to carry clinically actionable pathogenic sequence variants, testing also reveals enormous numbers of Unclassified Variants (UV), or Variants of Uncertain Significance (VUS), most of which are rare missense substitutions. Following IARC variant classification guidelines, quantitative methods have been developed to integrate multiple data types for clinical UV evaluation in BRCA1/2; results from these analyses are recorded in the BRCA gene Ex-UV database (hci-exlovd.hci.utah.edu). In variant classification the rate-limiting step is often accumulation of patient observational data. Recently, functional assays evaluating BRCA1 RING domain and C-terminal substitutions have been calibrated, enabling variant classification through a two-component combination of sequence analysis-based predictions with functional assay results. This two-component classification was embedded in a decision tree with safeguards to avoid misclassification. For the two-component analysis, sensitivity is 89.5%, specificity is 100%, and the error rate 0.0%. Classification of UV as likely pathogenic or likely neutral does not require certainty; the probabilistic definitions of the categories imply an error rate. Combining sequence analysis with functional assay data in two-component analysis added 154 BRCA1 variants to the Ex-UV database.