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Denaturing gradient gel electrophoresis-based analysis of loss of heterozygosity distinguishes nonobvious, deleterious BRCA1 variants from nonpathogenic polymorphisms.

BRCA1 is a tumor suppressor gene (1) responsible for one-half of familial breast/ovarian cancer syndromes and 40% of breast-only cancer syndromes (2)(3). BRCA1 codes for a 220-kDa nuclear phosphoprotein that has been suggested to play a role in cellular processes, including DNA repair and recombination (4)(5), transcriptional regulation (6)(7), and appropriate chromosomal segregation (8). It is unclear which of BRCA1 functions are important for decreasing breast/ovarian cancer susceptibility.

BRCA1 testing and genetic counseling services are offered to families with histories of breast and/or ovarian cancer (9). The available screening methods to detect germ-line BRCA1 mutations are expensive and time consuming because the gene is large, prevalent BRCA1 mutations are not found (except in ethnic communities), and mutations are scattered throughout the coding sequence (10).

Gene screening often detects a BRCA1 variant that does not imply a frameshift or a splicing alteration but represents a missense mutation not previously reported or registered in the Breast Cancer Informative Core Database (11). To address the question of whether these mutations represent new cancer-predisposing mutations or rare polymorphisms, one must consider characteristics such as absence of the variant in a control group of sufficient size, cosegregation with cancer in some families, and occurrence in a highly conserved protein sequence or in a putative functional domain. These considerations imply the study of large-pedigree families, which very often are not available and the conclusions of which are not always compatible with genetic counseling practice. As an indication of these limitations, only BRCA1 missense mutations that abolish the BRCA1 C-terminal transcriptional activity in a transfection assay (12) or disturb the RING-finger domain structure (13) have been defined as cancer-predisposing mutations (11). The lack of complete understanding of BRCA1 makes it difficult to design a reliable BRCA1 functional test similar to …