The cancer association of most alleles of BRCA1 carrying missense mutations is unknown, thus creating significant problems for genetic counseling. To increase our ability to identify cancer-associated mutations, Mirkovic et al. developed, validated, and applied a decision tree for predicting functional consequences of missense mutations in BRCA1. The picture shows the structure of the BRCA1 BRCT domains with the conservation of structure (among BRCT domains) and sequence (among BRCA1 orthologs) indicated by the intensity of blue color on the left and right panels, respectively. The solvent-exposed residues whose mutations are known to affect and not affect the transcriptional activation activity of BRCA1 are contoured in red and yellow, respectively. The region in violet on the left panel corresponds to the linker between the two domains. For details, see the article by Mirkovic et al. on page 3790 of this issue.

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