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

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.

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

“…In clinical settings, the limiting factor has shifted from acquisition of sequencing data to classification, interpretation, and reporting of novel and recurring sequence variants with little or no conclusive information supporting causation. 1 Classification of sequence variants considers the prevalence of the variant in presumably healthy unaffected individuals, cosegregation of the variant with disease in families, and computational and in vitro/in vivo analyses showing the predicted effect of the variant on function or aberrant splicing. 2 In particular, the frequency of occurrence, or lack thereof, of a variant in the general population (controls) constitutes an important line of evidence impacting variant classification.…”

Rapid de novo aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation

“…However, the amino acid change caused by the mutation (p.Arg1758Gln) impacts a highly conserved arginine residue in the myosin heavy chain 11 protein, which strongly suggests this mutation may be pathogenic. 2 Although MYH11 mutations are associated with TAAD, an association with cerebral aneurysms has not been reported. The patient featured in this report represents an index case and may shed light on an important molecular pathway that leads to the formation of cerebral aneurysms in children.…”

Professionally Responsible Disclosure of Genomic Sequencing Results in Pediatric Practice

“…Laboratories differ in their interpretations of genes of uncertain significance and variants of uncertain significance. 6 Efforts are underway to standardize interpretation of genetic variants through new guidelines from the American College of Medical Genetics and Genomics and through sharing of data across laboratories in ClinVar. 7 Individual laboratories determine which variants are initially reported.…”