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Genetic predisposition accounts for only a fraction of breast cancers, but genetic testing, in the appropriate context, is the most powerful tool available for quantitative risk stratification. The information provided by genetic testing contributes directly to risk management decisions and, frequently, to decisions about cancer treatment. BRCA1 and BRCA2 are still responsible for the majority of hereditary breast cancer cases, but the list of rare genes is increasing rapidly. The commercialization of massive parallel sequencing tests (i.e., next generation sequencing) has revolutionized genetic testing. Panel testing is becoming more common and patients are presenting more frequently with rare mutations in genes like CHEK2, PALB2, and ATM.

The introduction of paradigm-shifting technology is often associated with a period of controversy and uncertainty as the technology finds its place. This is true for next generation sequencing as well. Little data is available to accurately estimate cancer risks for many of the new genes and a high rate of uninterpretable results (i.e., variants of uncertain clinical significance) is expected. These issues will be resolved over time. The value of professional genetic counselors cannot be overstated in this period of uncertainty. This chapter provides an overview of recent advances in genetic testing as well as information about the new syndromes clinicians are encountering.


Lifetime breast cancer risk is only 13% for identical twins of breast cancer patients as compared to 9% for dizygotic twins.1 Similar twin studies estimate that 12% to 30% of breast cancer is primarily genetic in origin2,3 and modeling studies implicate autosomal dominant inheritance of single genes as the most important mechanism.4,5 These data suggest that environment (e.g., reproductive factors) accounts for a greater number of breast cancers than genetics. Despite enormous advances in gene sequencing, it is estimated that only 35% of apparently familial breast cancer is accounted for by known mutations (Fig. 68-1).6 The balance is likely accounted for by very rare moderately penetrant single gene mutations or by inheritance of combinations of low-penetrance mutations (i.e., polygenetic mechanism). Genome-wide association studies have convincingly identified 21 low-penetrance mutations or polymorphisms with relative risks in the range of 1.1 to 1.3.7-12 Increasing numbers of mutations in an individual is associated with increasing breast cancer risk with the greatest risk conferred by the rarer mutations.13


Genetic component of breast cancer. The proportion of apparently familial breast cancers attributable to mutations in major predisposition genes is estimated from unpublished Next Generation Sequencing test results.

Mutations in some genes, such as BRCA1 or TP53, are classified as highly penetrant; that is, most individuals inheriting the mutation will develop cancer. Nevertheless, penetrance can vary greatly by family for any of the genes. This is likely due to the ...

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