NEW YORK (GenomeWeb) – The Association for Molecular Pathology weighed in on the reporting of incidental findings from genome-scale clinical sequencing tests this week with a report by one of its working groups.
The report, published online in the Journal of Molecular Diagnostics today, comes three months after the American College of Medical Genetics and Genomics updated its recommendations for reporting incidental findings, which ACMG prefers to call secondary findings.
The AMP report, prepared by a joint working group of the association's clinical practice committee and the whole-genome analysis working group, discusses issues associated with incidental findings and makes recommendations for labs considering to report them.
The report, whose lead author Madhuri Hegde is the executive director of Emory Genetics Laboratory, adds to two recent publications — by members of the National Heart Lung and Blood Institute's Exome Sequencing Project and the Baylor-Hopkins Center for Mendelian Genomics — on their experience with incidental findings.
While ACMG recommends the review of variants in 56 genes for anyone undergoing large-scale genomic testing, the AMP report points out that doing so requires a significant effort on the part of laboratories, and even more so if family members are included in the analysis. Also, confirming incidental findings by Sanger sequencing adds to the cost of testing and increases turnaround time.
Current shortcomings of next-gen sequencing also limit the accuracy of testing for the 56 ACMG-recommended genes. At least eight of these genes have one or more pseudogenes associated with them, for example, and confirmatory testing may be required to ensure that variants found in these genes don't derive from the pseudogenes.
Another issue is that studies have found many patients do not wish to receive incidental findings for several reasons, including unknown health implications in different population groups, increased distress to patients already dealing with disease, and fear of not being able to get life, long-term care, or disability insurance.
Some argue that incidental findings in genomic tests are similar to incidental findings in other areas of medicine, such as radiology, but the AMP authors note that the two are "fundamentally different, one being unavoidable and the other requiring additional analysis and interpretation" – possibly the reason ACMG has switched its terminology to 'secondary findings.'
To avoid any confusion for patients and providers, laboratories offering clinical genomic testing should clearly indicate on their consent form whether they routinely analyze the ACMG-recommended 56 genes, or whether they analyze fewer or more genes. The consent should also make clear whether patients can opt in or out of receiving secondary results.
In addition, patients should be informed about the "numerous limitations" of exome sequencing, which does not cover all genes, and not all equally well. Labs should also make clear what types of variants — such as pathogenic, likely pathogenic, or variants of unknown significance — they will report, and whether these differ between primary test results and incidental findings.
Further, the consent should "clearly state the psychological risks and risks of insurance discrimination" that could result from incidental findings.
While clinical laboratories have to comply with federal and state regulations, such as CLIA, the report points out that regulatory agencies "have not addressed the issue of reporting incidental findings" to date. But according to CLIA requirements, labs need to validate all reported findings, whether related to the test indication or not.
Finally, as genomic testing continues to enter the clinic, stakeholders such as practitioners, lab pathologists, patients, policy makers, and payors, need to be educated about the implications of incidental findings, and education programs should be developed in conjunction with professional societies.
In its recommendations, the working group states that laboratories providing NGS services must develop a policy for analyzing and reporting incidental findings, and should offer patients opt-in or opt-out opportunities.
For now, it recommends that all reported variants be confirmed by an alternative method, such as Sanger sequencing, though as NGS technology improves, "it is likely that these recommendations will change."
Only pathogenic or likely pathogenic variants should be included in the report of incidental findings, and they should be clearly labeled in the full test report and explained to physicians in an accessible way.
Over time, the report concludes, "it is likely that recommendations from professional societies [regarding incidental findings] will evolve as NGS technology matures, genomic education improves, and regulatory authorities and other groups refine the standards for laboratory medicine with respect to genomic analysis."