Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines.

Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene panel testing for hereditary cancer risk. Although genetic testing helps guide clinical diagnosis and management, testing recommendations are based on personal and family history of cancer and ethnicity, and many carriers are being missed. Herein, we report the results from 23,179 individuals who were referred for 30-gene next-generation sequencing panel testing for hereditary cancer risk, independent of current testing guidelines-38.7% of individuals would not have met National Comprehensive Cancer Network criteria for genetic testing. We identified a total of 2811 pathogenic variants in 2698 individuals for an overall pathogenic frequency of 11.6% (9.1%, excluding common low-penetrance alleles). Among individuals of Ashkenazi Jewish descent, three-quarters of pathogenic variants were outside of the three common BRCA1 and BRCA2 founder alleles. Across all ethnic groups, pathogenic variants in BRCA1 and BRCA2 occurred most frequently, but the contribution of pathogenic variants in other genes on the panel varied. Finally, we found that 21.7% of individuals with pathogenic variants in genes with well-established genetic testing recommendations did not meet corresponding National Comprehensive Cancer Network criteria. Taken together, the results indicate that more individuals are at genetic risk for hereditary cancer than are identified by current testing guidelines and/or use of single-gene or single-site testing.

Black cohosh-induced hepatitis.

Herbal products are widely used by American consumers. Herbal remedies are not regulated by the Food and Drug Administration, but they are not immune from serious medication side-effects. We report the case of a 50-year-old woman who presented with fatigue and right upper quadrant pain. The patient had begun the popular postmenopausal herbal remedy black cohosh two weeks prior to presentation. Laboratory results revealed acute hepatitis. After other causes of liver failure were ruled out, the patient was diagnosed with black cohosh-induced hepatitis. She recovered uneventfully following withdrawal of the herb. There are five prior reports of hepatitis or hepatic failure likely caused by the herbal remedy black cohosh in the English literature. This case illustrates the importance of a broad differential diagnosis for abdominal pain and highlights the importance of a complete medication list, including herbs.