Don't Just Invite Us to the Table: Authentic Community Engagement

Abstract

uch has been written about incidental findings be-cause they are a common result of increased use ofexome and genome sequencing. In March 2013, the AmericanCollege of Medical Genetics and Genomics (ACMG) pub-lished a policy statement on the topic. A Working Group onIncidental Findings in Clinical Exome and Genome Sequen-cing made ‘‘recommendations about responsible manage-ment of incidental findings when patients undergo exome orgenome sequencing’’ (Green et al., 2013). Their deliberation,which included review by outside experts, took a year toproduce recommendations that were then approved by theACMG Board of Directors.The reportrecommends that laboratories performingclinicalsequencingseekandreportmutationsofthespecifiedclassesortypes in 57 genes causing 24 phenotypes named in the report.The working group, composed of medical and laboratory ge-neticists, recommended that reporting be performed for ‘‘allclinical germline (constitutional) exome and genome sequenc-ing, including the ‘normal’ of tumor-normal subtractive analy-ses in all subjects, irrespective of age, but excluding fetalsamples.’’ The Working Group recognized that data on clinicalutility are insufficient to fully support their recommendations.In the dynamically changing field of genetics and genomics,they encouraged the creation of an ongoing process for updat-ing these recommendations at least annually.Recommendations1. Constitutional mutations found in the genes on theminimum list (see Table) should be reported by thelaboratory, regardless of the indication for which theclinical sequencing was ordered.a. Additional genes may be analyzed for incidental(secondary) variants, as deemed appropriate by thelaboratory.b. Incidental (secondary) variants should be reportedregardless of the age of the patient.c. Incidental (secondary) variants should be reportedfor any clinical sequencing conducted on a constitu-tional (but not tumor) tissue. This includes the nor-mal sample of a tumor-normal sequenced dyad andunaffected members of a family trio.2. The Working Group recommends that laboratories seekand report only the types of variants within these genesthat we have delineated (see Table).a. For most genes, only variants that have been previ-ously reported and are a recognized cause of thedisorder or variants that are previously unreportedbut are of the type which is expected to cause thedisorder, as defined by prior ACMG guide-lines.should be reported.b. For some genes, predicted loss of function variantsare not relevant (e.g., COL3A1 and most hypertro-phic cardiomyopathy genes).c. For some genes (e.g., APOB), laboratories shouldonly report variants for certain conditions.3. It is the responsibility of the ordering clinician/team toprovide comprehensive pre- and post-test counseling tothe patient.a. Clinicians should be familiar with the basic attributesand limitations of clinical sequencing.b. Clinicians should alert patients to the possibility thatclinical sequencing may generate incidental findingsthat could require further evaluation.c. Given the complexity of genomic information, theclinical geneticist should be consulted at the appro-priate time that may include ordering, interpreting,and communicating genomic testing.4. These recommendations reflect limitations of currenttechnology, and are therefore focused on disorders thatare caused by point mutations and small insertions anddeletions, not those primarily caused by structuralvariants, repeat expansions, or copy number variations.5. The Working Group recommends that the ACMG, to-gether with content experts and other professional or-ganizations, refine and update this list at least annually.Certainly a great deal of commentary will be written aboutthe recommendations themselves. This perspective piececomments on the process of determining the recommenda-tions.Therecommendationswereestablishedthroughalongandthoughtfuldeliberationofexpertsinthefieldofgenetics,bothfrom laboratory and clinical perspectives. Outside experts,again geneticists, reviewed the recommendations before theywere published. This is laudable. The individuals involvedsmartly anticipate the onslaught of information that willaccompany exome and genome sequencing as it moves rap-idly into clinical settings. They were bold in making re-commendations in areas that lacked traditional clinical utility