Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM1, Dorschner MO2, Robertson PD3, Salama JS1, Hart R1, Shirts BH4, Murray ML5, Tokita MJ1, Gallego CJ1, Kim DS6, Bennett JT7, Crosslin DR6,Ranchalis J1, Jones KL8, Rosenthal EA1, Jarvik ER1, Itsara A1, Turner EH9, Herman DS4, Schleit J10, Burt A1, Jamal SM11, Abrudan JL12, Johnson AD13,Conlin LK14, Dulik MC15, Santani A14, Metterville DR16, Kelly M17, Foreman AK18, Lee K18, Taylor KD19, Guo X19, Crooks K20, Kiedrowski LA21, Raffel LJ22,Gordon O22, Machini K23, Desnick RJ24, Biesecker LG25, Lubitz SA26, Mulchandani S27, Cooper GM28, Joffe S29, Richards CS30, Yang Y31, Rotter JI19, Rich SS32, O'Donnell CJ33, Berg JS18, Spinner NB14, Evans JP18, Fullerton SM34, Leppig KA35, Bennett RL1, Bird T36, Sybert VP37, Grady WM38, Tabor HK39, Kim JH40, Bamshad MJ41, Wilfond B42, Motulsky AG6, Scott CR43, Pritchard CC4, Walsh TD1, Burke W44, Raskind WH45, Byers P5, Hisama FM1, Rehm H46,Nickerson DA3, Jarvik GP47.

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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.