COLUMBUS, OHIO (GenomeWeb) – As more is uncovered about the roles that genetic variants play in health and disease, variants that were once thought to be pathogenic or whose effects were unclear have turned out to be benign, while a portion thought to be benign have turned out not to be.
Genetic counselors are beginning to tease out how common it is for a variant to be re-assigned as well as how such a change affects patients, according to speakers at session on variant classification at the National Society of Genetic Counselors annual meeting here Friday afternoon.
"In the clinic, we have come across this for several families now, " said Ashley Parrott, a genetic counselor at Cincinnati Children's Medical Hospital.
But Nicole Brown, a genetic counselor at Myriad Genetic Laboratories, noted that there is little data regarding the frequency of variant reclassification and their clinical impact. "This leaves providers with little guidance," she said.
While still at the University of Texas Southwestern Medical Center, Brown and her colleagues worked with Myriad to gauge how often variants are reclassified. They drew upon a clinical cohort of nearly 1.5 million people who'd undergone hereditary cancer genetic testing between 2006 and 2016. The vast majority of the cohort was female and slightly more than half were of European descent.
For these 1.5 million people, Myriad generated nearly 1.7 million initial reports, as some people took more than one test. Within the time frame the researchers studied, 59,942 amended reports were issued. The subset of this cohort that was from UT Southwestern — 8,427 people — led to 9,545 initial reports and 579 amended reports.
"They are not terribly different," Brown said of the two groups.
Overall, nearly 20 percent of reported variants were reclassified. Most reports were amended because a variant had been downgraded, according to Brown — a pathogenic or likely pathogenic variant became a variant of uncertain significance or even a benign variant, or a VUS became a benign or likely benign variant. Downgrades accounted for 94.5 percent of the amended reports among the full cohort. Only 4.5 percent of the amended reports were due to variants being upgraded.
"When a comprehensive classification approach is employed, variant reclassification is relatively common in genetic testing for hereditary cancer risk," Brown noted.
Additionally, she found that of the VUS that were reclassified, 91.5 percent were downgraded and only 8.5 percent were upgraded in the full cohort. The UT-Southwestern subset, meanwhile, had an even higher percentage of downgraded VUS.
But what does this reclassification mean for patients and their families? Cincinnati Children's Parrott and her colleagues surveyed about a dozen people about how having their variant reclassified affected them. They invited patients who had met with a genetic counselor at their institute between January 2011 and July 2016 and who had had a positive or a negative finding reclassified. An average 4.2 years had elapsed between patients' initial results and being informed of a change in their variant's status.
Parrott found that people responded with a range of emotions. Some people expressed worry or anxiety, while others were disappointed, upset, or felt regret. Yet others felt relief.
In the surveys, people related disappointment that there was no longer a cause or etiology for their disease, while others regretted the time and resources they had spent on a condition they were no longer considered to be at risk for. Other respondents were devastated to find they were now at risk for a condition they'd thought they'd dodged.
Some respondents also expressed frustration with researchers and healthcare providers, saying that they felt like they kept changing their minds. Parrott did note, however, that another respondent was grateful that there was ongoing research.