Germ-line mutations in BRCA1 account for the majority of familial breast and ovarian cancer cases and development of cancer in individuals who carry such mutations requires somatic inactivation of the normal allele. BRCA1 is highly polymorphic with more than 1,200 distinct documented variants. Approximately 70% of reported variants lead to absence of full-length BRCA1 protein, through loss of expression or protein truncation, and are suspected to predispose to cancer. These include regulatory mutations, splice site alterations, large rearrangements, large and small deletions or insertions, and nonsense mutations. However, characterizing the remaining missense alterations as either deleterious (cancer-associated mutations) or neutral variants is more complex, as the functional significance of the respective amino acid substitution is not straightforward to evaluate. In addition, many missense variants have been identified only once in defined ethnic groups and represent alleles with very low frequency. Most often, little information is available about segregation of the variant with disease in families, and assessment of disease risk for low frequency alleles through association studies is problematic, requiring a large number of samples stratified and matched by ethnicity. The fact that a significant proportion of BRCA1 variants remain unclassified represents a gap in risk assessment, such that individuals undergoing genetic testing will receive noninformative test results. An approach for assessing the potential clinical significance of missense variants is to combine available genetic data with functional and structural studies. Here we review the available information on BRCA1 variants and explore ways in which we can analyze unclassified variants.