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New Data Underscores Volatility of Variant Classification, Highlights Need for Regular Reanalysis

NEW YORK (GenomeWeb) – A large retrospective study of patients tested for hereditary cancer mutations by Myriad Genetics has elucidated how elastic the process of genetic variant classification is, highlighting the need for making regular updates to classification databases, and ideally sending these updates to the individuals who have received these results.

Researchers reported in JAMA today that nearly 25 percent of the variants of uncertain significance Myriad returned to customers between 2006 and 2016 were at some point reclassified, including both downgrades — to benign or likely benign — and upgrades to pathogenic or likely pathogenic.

The fluidity of genetic variant classification is one feature that sets clinical genomics apart from the rest of the medical testing field. Because our understanding of the function of various portions of genetic code is still evolving, the results returned to individuals who have had a genetic test are far from static. Reclassifications can arise from the collection of multiple new cases or families in the literature, from functional lab studies, or from new understanding of biochemistry.

"We are getting new data all the time," Theo Ross, professor of internal medicine at UT Southwestern and senior author of the new study, said in a statement.

The authors wrote that their results underscore the need for testing labs to periodically review their records and alert physicians when scientific knowledge evolves. A reclassification from VUS to benign, though not necessarily dangerous to miss, might provide invaluable peace of mind to patients. On the other hand, if a variant is reclassified as pathogenic, failing to inform patients could lead to significantly negative consequences.

"The implications of this study are three-pronged. Physicians need to be aware of how rapidly knowledge about gene variants is advancing and that reclassifications are common. Labs need to review gene variant information on a regular basis and alert physicians to changes. Finally, patients and their family members need to be made aware of reclassifications by their physicians, so they can make well-informed choices," Ross added.

The question remains, however, just how often and how doggedly labs must seek to update classifications, and more importantly to inform previously tested customers that their results have been updated.

In the JAMA study, the investigators attempted to add context to this question by reviewing Myriad's records for patients tested over a period of 10 years. The resulting cohort totaled more than 1.5 million individuals, most of whom were tested using a single-gene or small panel test, and about 300,000 of whom received the company's larger multi-gene panel.

Myriad used an automated, ongoing system to identify new evidence that could affect variant classification. Over the study period, very few variants were either upgraded from a benign or likely-benign classification or downgraded from a pathogenic or likely-pathogenic classification — 0.2 percent and 0.7 percent respectively.

In contrast, among the 27,000 or so variants of unknown significance that were returned to customers, 7.7 percent were later reclassified. And because many of these variants affected more than one individual, the reclassifications ended up affecting a full 25 percent of the cohort's clinical reports. More than 90 percent of the VUS reclassifications (1,867 reports) were downgrade to a benign category, while the remainder featured an upgrade to a pathogenic result.

The understanding that initial variant classifications are not static is far from new, and the challenges of how to make sure reclassifications happen in a timely manner, with appropriate communication to patients, has already been a subject of ongoing discussion in the genetic testing community. Legal challenges have even emerged that hinge upon laboratory obligations for variant reclassification and patient communication.

For its part, the JAMA study provided a new, comprehensive picture of the shape and frequency of the issue, especially considering the increasing numbers of individuals who are now receiving genetic testing for hereditary cancer risk and other conditions.

In a statement highlighting the publication, Myriad Vice President of Medical Services Susan Manley argued that the study results underscored "the need for clinicians to use a clinical laboratory that provides timely variant reclassification information to ensure appropriate medical care of patients and their relatives."

But because the study focused only on one company's archives, it left open the question of how much various commercial and academic testing labs may diverge in their practices in this regard.