Conclusion

Mutation detection in the BRCA1 and BRCA2 genes is of great clinical import but is extremely challenging from a technical standpoint. The large variety of mutation types mandates the use of multiple mutation detection methods if a sensitivity approaching 100% is desired. Methods for assessing pretest probability based on clinical presenta-tion33 can be used to determine which cases merit the highest degree of mutational analysis. Further improvements in mutation detection methods are needed to clarify the true sensitivity of testing versus the proportion of families with mutations in other hereditary breast cancer genes. Clinical interpretation is beleaguered by the high prevalence of genetic variants of uncertain significance. Development of functional assays is highly desirable and may help classify variants into benign or disease-causing categories.

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