To evaluate the functional significance of human BRCA1 and BRCA2 variants and to carry out functional dissection of these proteins, we have developed a simple, reliable and physiologically relevant functional assay using mouse embryonic stem (ES) cells. The assay is based on the fact that Brca1 and Brca2-null ES cells cannot survive. Therefore we engineered ES cells to express a conditional allele of Brca1 or Brca2. Desired mutations are generated in the human BRCA1 or BRCA2 gene in bacterial artificial chromosomes (BAC) and introduced into the ES cells. Functional analysis is performed after deletion of the conditional allele. The ability of and the extent to which specific variants complement the lethality of ES cells associated with Brca1 or Brca2 deficiency is used to evaluate their functional significance. Variants that can rescue lethality are then screened for a defect in the known functions of BRCA1 and BRCA2.