RT Journal
A1 Amendola, Laura M.
A1 Dorschner, Michael O.
A1 Robertson, Peggy D.
A1 Salama, Joseph S.
A1 Hart, Ragan
A1 Shirts, Brian H.
A1 Murray, Mitzi L.
A1 Tokita, Mari J.
A1 Gallego, Carlos J.
A1 Kim, Daniel Seung
A1 Bennett, James T.
A1 Crosslin, David R.
A1 Ranchalis, Jane
A1 Jones, Kelly L.
A1 Rosenthal, Elisabeth A.
A1 Jarvik, Ella R.
A1 Itsara, Andy
A1 Turner, Emily H.
A1 Herman, Daniel S.
A1 Schleit, Jennifer
A1 Burt, Amber
A1 Jamal, Seema M.
A1 Abrudan, Jenica L.
A1 Johnson, Andrew D.
A1 Conlin, Laura K.
A1 Dulik, Matthew C.
A1 Santani, Avni
A1 Metterville, Danielle R.
A1 Kelly, Melissa
A1 Foreman, Ann Katherine M.
A1 Lee, Kristy
A1 Taylor, Kent D.
A1 Guo, Xiuqing
A1 Crooks, Kristy
A1 Kiedrowski, Lesli A.
A1 Raffel, Leslie J.
A1 Gordon, Ora
A1 Machini, Kalotina
A1 Desnick, Robert J.
A1 Biesecker, Leslie G.
A1 Lubitz, Steven A.
A1 Mulchandani, Surabhi
A1 Cooper, Greg M.
A1 Joffe, Steven
A1 Richards, C. Sue
A1 Yang, Yaoping
A1 Rotter, Jerome I.
A1 Rich, Stephen S.
A1 O’Donnell, Christopher J.
A1 Berg, Jonathan S.
A1 Spinner, Nancy B.
A1 Evans, James P.
A1 Fullerton, Stephanie M.
A1 Leppig, Kathleen A.
A1 Bennett, Robin L.
A1 Bird, Thomas
A1 Sybert, Virginia P.
A1 Grady, William M.
A1 Tabor, Holly K.
A1 Kim, Jerry H.
A1 Bamshad, Michael J.
A1 Wilfond, Benjamin
A1 Motulsky, Arno G.
A1 Scott, C. Ronald
A1 Pritchard, Colin C.
A1 Walsh, Tom D.
A1 Burke, Wylie
A1 Raskind, Wendy H.
A1 Byers, Peter
A1 Hisama, Fuki M.
A1 Rehm, Heidi
A1 Nickerson, Debbie A.
A1 Jarvik, Gail P.
T1 Actionable exomic incidental findings in 6503 participants: challenges of variant classification
JF Genome Research 
JO Genome Research 
YR 2015 
FD March 01 
VO 25 
IS 3 
SP 305 
OP 315 
DO 10.1101/gr.183483.114 
UL http://genome.cshlp.org/content/25/3/305.abstract 
AB 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.