Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes

Abstract

Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family-history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups.

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

“…Furthermore, it is not clear how individual attributes of a pLOF variant (e.g., predicted NMD, position of variant in gene, or presence of variant in an obligate exon) are correlated to pathogenicity in individuals. Although prior clinical reports are often used to support pathogenicity for specific variants, it is clear that not all reported pathogenic mutations cause disease 13 and that the absence of prior clinical reports of pathogenicity is not sufficient to refute causation. For the group of individuals that could be assessed for findings of disease, variants were classified as either positive or negative.…”

Clinical Genomic Database

“…However, genomic sequencing has myriad potential applications in more general clinical medicine, including in healthy individuals (3)(4)(5)(6)(7)(8).…”

Incomplete Knowledge of the Clinical Context as a Barrier to Interpreting Incidental Genetic Research Findings

“…Family histories that are informed by multiple sources and/or updated periodically are even rarer. As in the case described here, knowledge of the family history may (1) demonstrate that a potential increased risk for a disease based on molecular findings is already known on the basis of a positive family history (Costain and Bassett 2012), (2) reveal information critical to the proper interpretation of an incidental finding in a study participant (Johnston et al 2012), and/or (3) clarify potential responsibilities of the researchers to other family members. With the typical absence or incompleteness of these data in research studies, a duty to search for incidental findings in a research participant could conceivably lead to researchers investing significant resources in context-less follow-up and expensive though clinically needless molecular testing.…”

“…In our case, knowledge of the previous clinical diagnoses and treatment of familial hypercholesterolemia allowed us to better gauge the potential benefit to the participants of returning the incidental LDLR genetic finding. Many studies focused on interpreting incidental genetic findings have also implicitly or explicitly used detailed clinical (and family history) information (see, e.g., Johnston et al 2012;Solomon et al 2012), but to our knowledge this context would be practically unavailable to most current genetic researchers in most cases.…”

“…For example, this could include a typical mutation in the BRCA1 gene known to predispose to breast and ovarian cancer in a young woman with no personal or family history of either cancer (Johnston et al 2012). However, most rare variants of potential clinical import are private (seemingly unique to the individual or family) and ultimately found to be inherited.…”