Why Cancer Gene Variants are Frequently Reclassified

Gene variants of uncertain significance are frequently reclassified, necessitating amended test result reports, according to a retrospective analysis of Myriad Genetics lab data published in JAMA.

“Overall, 24.9% of all reported variants of uncertain significance were reclassified” over a 10-year period, reported senior study coauthor Theodora Ross, MD, PhD, of the University of Texas Southwestern Medical Center in Dallas. In more than 90% of cases, variants of uncertain significance findings were classified downward, to benign or likely benign.

“Physicians need to be aware of how rapidly knowledge about gene variants is advancing and that reclassifications are common,” Ross said. “Labs need to review gene variant information on a regular basis and alert physicians to changes.”

Patients should be alerted to reclassifications and their clinical implications in order to avoid ongoing anxiety and inappropriate treatment, Ross said.

“This is a very important study highlighting the inadequacy of our knowledge of variants of uncertain significance results,” Vivek Subbiah, MD, at the University of Texas MD Anderson Cancer Center in Houston told Cancer Network.

The authors retrospectively reviewed 1.45 million individuals’ genetic testing records dated from 2006–2018, for whom 1.67 million tests were reported. Six percent (2868 of 44,777) of unique variants were reclassified overall. Reclassification was rare for variants initially classified as pathogenic or likely pathogenic (0.7%), and even rarer for those classified as benign or likely benign (0.2%).

However, variants of uncertain significance reclassification was more common, affecting 7.7% of variants (2048 variants of uncertain significance reclassifications of 26,670 unique variants).

Timely reclassification from variants of uncertain significance to benign can minimize the risk of unnecessary anxiety and treatments, Subbiah noted.

All gene tests should be reviewed for possible reclassification, Ross said. Gene variant analysis can be automated and archived in databases, alerting scientists and clinicians to new information about a particular variant of uncertain significance.

Patients should be told about the variants of uncertain significance reclassification findings, Ross believes. “I would add it to their reading list,” she said.

Because the study was a single-center retrospective review, more research is needed.

But, the findings show a national database or program is needed that “accurately classifies and reclassifies variants of uncertain significance, Subbiah said.

“Clinicians, genetic counselors, and patients should be educated to ensure up-to-date clinical management and possibly to develop national guidelines or algorithms to reduce hereditary cancer risk,” Subbiah said.