Clinical genetic testing is increasingly employed in the medical management of cancer patients. These tests support a variety of clinical decisions by providing results that indicate risk for future disease, confirmation of diagnoses, and more recently, therapeutic selection and prognosis. Most genetic variation detected during clinical testing involves single nucleotide polymorphisms (SNPs). Continued advances in the technologies of genetic analyses make these tests increasingly sensitive, cost-effective and timely, which contribute to their increased utilization. Conversely, it has proven difficult to characterize the clinical significance of genetic variants that do not obviously truncate the open reading frames of genes. These genetic variants of uncertain clinical significance diminish the value of genetic test results. This article highlights a variety of approaches that have emerged from research in diverse disciplines to solve the problem, including the application of information about common SNPs in multiple methods to better characterize clinically uncertain variants. Hereditary breast/ovarian cancer, and in particular BRCA1, provides a framework for this discussion. BRCA1 is particularly interesting in this respect since clinical genetic testing by direct DNA sequencing for over 50,000 patients in North America has revealed approximately 1500 genetic variants to date. This large data set combined with the clinical significance of BRCA1 have resulted in research groups selecting BRCA1 as a preferred gene to evaluate novel methods in this field. Finally, the lessons learned through work with BRCA1 are highly applicable to many other genes associated with cancer risk.