A total of 565 genes were chosen for analysis on the basis of review of the American College of Medical Genetics and Genomics (ACMG) gene list and the medical literature1 (link)-4 and were divided into five nonoverlapping categories (Fig. 2 ; and Table S3 in Supplementary Appendix 1 and Table S2 in Supplementary Appendix 2 , available at NEJM.org ). The first category included genes that have been associated with autosomal dominant cancer-predisposition syndromes, and it consisted of 49 classical genes (including 23 genes from the ACMG gene list5 (link)) and 11 genes that have been implicated in genetic syndromes associated with RAS mutations (sometimes called RASopathies; these include the cardiofaciocutaneous syndrome, Costello’s syndrome [also called the faciocutaneoskeletal syndrome], Noonan’s syndrome, and the multiple lentigines syndrome). These 60 genes were selected because of the potential effect of germline mutations on clinical practice, including avoidance of radiation therapy, choice of surgical approach for tumor resection, donor testing and selection for hematopoietic stem-cell transplantation, possible or proven benefits of tumor surveillance and early cancer detection, and risk-reductive surgery.3 Variants detected in these 60 genes were confirmed experimentally by an independent sequencing assay (Supplementary Appendix 1 ).
The second category included 29 genes that have been associated with autosomal recessive cancer-predisposition syndromes, with a focus on identifying biallelic pathogenic mutations. Variants detected in the 89 genes that have been associated with autosomal dominant or autosomal recessive cancer-predisposition syndromes were reviewed by a multidisciplinary panel for classification and reporting.5 (link)-8 (link)An additional 476 genes were chosen for evaluation on the basis of their recurrent somatic mutation in cancer (http://cancer.sanger.ac.uk/cancergenome/projects/census and www.pediatriccancergenomeproject.org/site ). These genes were classified into three categories: tumor-suppressor genes (58 genes),9 (link) tyrosine kinase genes (23), and other cancer genes (395). Our analyses of the genes in these three categories focused on known hotspot-activating mutations in genes encoding kinases and on truncation mutations in genes encoding tumor-suppressor proteins and in other cancer genes.
The second category included 29 genes that have been associated with autosomal recessive cancer-predisposition syndromes, with a focus on identifying biallelic pathogenic mutations. Variants detected in the 89 genes that have been associated with autosomal dominant or autosomal recessive cancer-predisposition syndromes were reviewed by a multidisciplinary panel for classification and reporting.5 (link)-8 (link)An additional 476 genes were chosen for evaluation on the basis of their recurrent somatic mutation in cancer (
