Clinical Tumor Sequencing: An Incidental Casualty of the American College of Medical Genetics and Genomics Recommendations for Reporting of Incidental Findings

Germline Analysis from Tumor–Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings

“…The other half, representing about ~2% of our patients, were not associated with any prior clinical hereditary cancer evaluation. For this subset of patients, the opportunistic germline analysis provides critical information for both the individual and their family, enabling potentially lifesaving interventions(9,33). Identifying pathogenic germline variants could also provide important prognostic information, guiding surgical procedures or targeted therapeutic options for the individual cancer patient, thereby providing immediate treatment applications(2,34).…”

“…Ultimately, in a setting such as tumor-germline sequencing returning VUS results to patients would produce a significant clinical burden(33), may cause undue stress, and may result in potentially unnecessary surveillance, testing or procedures for the patient and family members erroneously presumed to be “at-risk”. Given the more stringent threshold for reporting of variants considered to be incidental or secondary to the testing indication, it is essential to recognize that the absence of a reported germline hereditary cancer variant on a tumor-germline test does not rule out the possibility that a pathogenic variant does, in fact, exist.…”

Patient preferences regarding incidental genomic findings discovered during tumor profiling

“…In response to the ensuing academic debate and call for revision from numerous genetic professionals and providers , the ACMG guidelines were re-issued the following year and an opt-out policy was recommended for patients who did not want to discover incidental findings [10][11][12][13][14].…”

“…In this setting, oncology patients are pursuing tumor profiling with the sole intention of finding new therapeutic options for their disease, rather than for specific examination of their germ-line DNA. Some in the oncology community suggest that reporting of incidental germ-line variants discovered as part of tumor profiling would substantially increase time expenditure, expense, and complexity of an already burdened clinical setting, and may negatively impact patients to the point where they may opt out from tumor testing altogether [14][15][16]. Others cite the debate as to whether there exists an obligation for laboratories to actively seek and report medically relevant germ-line mutations as outlined by the ACMG, particularly given that most patients undergoing tumor profiling have advanced disease and are themselves unlikely to benefit from the information on heritable diseases [1,9,13].…”

Clinical Players and Healthcare Payers: Aligning Perspectives on the Cost–Effectiveness of Next-Generation Sequencing in Oncology

“…From the onset we acknowledge that there are potential ethical issues and economic impacts of reporting incidental findings from the normal sample of a tumor-normal sequenced dyad (see Parsons et al [2]). …”