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Background  Deleterious variants in the tumour suppressor  BRCA1  are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in  BRCA1  pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in  BRCA1  are located in the  BRCA1  C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12  BRCA1  variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants.    Results  Twelve  BRCA1  VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.5504G>A remained classified as VUSs (class 3).    Conclusions  The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.    Electronic supplementary material  The online version of this article (10.1186/s40246-018-0183-1) contains supplementary material, which is available to authorized users.

Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance