@article{Amendola01032015,
author = {Amendola, Laura M. and Dorschner, Michael O. and Robertson, Peggy D. and Salama, Joseph S. and Hart, Ragan and Shirts, Brian H. and Murray, Mitzi L. and Tokita, Mari J. and Gallego, Carlos J. and Kim, Daniel Seung and Bennett, James T. and Crosslin, David R. and Ranchalis, Jane and Jones, Kelly L. and Rosenthal, Elisabeth A. and Jarvik, Ella R. and Itsara, Andy and Turner, Emily H. and Herman, Daniel S. and Schleit, Jennifer and Burt, Amber and Jamal, Seema M. and Abrudan, Jenica L. and Johnson, Andrew D. and Conlin, Laura K. and Dulik, Matthew C. and Santani, Avni and Metterville, Danielle R. and Kelly, Melissa and Foreman, Ann Katherine M. and Lee, Kristy and Taylor, Kent D. and Guo, Xiuqing and Crooks, Kristy and Kiedrowski, Lesli A. and Raffel, Leslie J. and Gordon, Ora and Machini, Kalotina and Desnick, Robert J. and Biesecker, Leslie G. and Lubitz, Steven A. and Mulchandani, Surabhi and Cooper, Greg M. and Joffe, Steven and Richards, C. Sue and Yang, Yaoping and Rotter, Jerome I. and Rich, Stephen S. and O’Donnell, Christopher J. and Berg, Jonathan S. and Spinner, Nancy B. and Evans, James P. and Fullerton, Stephanie M. and Leppig, Kathleen A. and Bennett, Robin L. and Bird, Thomas and Sybert, Virginia P. and Grady, William M. and Tabor, Holly K. and Kim, Jerry H. and Bamshad, Michael J. and Wilfond, Benjamin and Motulsky, Arno G. and Scott, C. Ronald and Pritchard, Colin C. and Walsh, Tom D. and Burke, Wylie and Raskind, Wendy H. and Byers, Peter and Hisama, Fuki M. and Rehm, Heidi and Nickerson, Debbie A. and Jarvik, Gail P.}, 
title = {Actionable exomic incidental findings in 6503 participants: challenges of variant classification},
volume = {25}, 
number = {3}, 
pages = {305-315}, 
year = {2015}, 
doi = {10.1101/gr.183483.114}, 
abstract ={Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.}, 
URL = {http://genome.cshlp.org/content/25/3/305.abstract}, 
eprint = {http://genome.cshlp.org/content/25/3/305.full.pdf+html}, 
journal = {Genome Research} 
}