The Case for Reanalyzing Variant Calls

An analysis of genetic tests taken from 1.45 million individuals at a commercial lab in Utah revealed that nearly 25% of variants of uncertain significance (VUS) had been reclassified, pointing to a need for laboratories to stay on top of gene variant changes and inform doctors of any reclassifications. Researchers published their study results in the Journal of the American Medical Association (JAMA).

Opportunities for variation are vast, given that a gene typically contains large numbers of base pairs, sometimes numbering in the thousands or even millions. Variant pathogenicity in a gene can be classified as benign, likely benign, likely pathogenic, or pathogenic. There’s also a fifth classification, VUS. A shift from this classification to benign or pathogenic has huge implications for patients.

“If a variant is reclassified to being pathogenic, then it matters to the patient,” said the study’s senior author, Theodora Ross, MD, PhD, a professor of internal medicine at UT Southwestern Medical Center in Dallas, in a statement. “For example, if they have a broken Lynch syndrome gene, then they need different care from their doctor such as having colonoscopies at an earlier age or more frequently—sometimes as often as every year. Or, if they have a broken BRCA gene, they may want to have prophylactic surgery or add MRI scans to their mammogram screening program.”

Likewise, reclassifying a variant from VUS to benign can ease a patient’s concerns about his or her health. Doctors, however, have little information to guide them on the frequency and significance of variant reclassifications.

Ross and her team sought to find answers, reviewing test results for hereditary cancer genes from Myriad Genetic Laboratories, and related clinical data from UT Southwestern’s Cancer Genetics Program from 2006 to 2016. In the researchers’ assessment of 1.45 million patients and 1.67 million initial tests, they found that variant reclassification led to the issuance of nearly 60,000 amended reports.

A quarter of the reports initially classified as VUS had been reclassified. While most had been downgraded to less severe classifications, nearly 9% received upgrades to more severe classifications, such as likely pathogenic or pathogenic. In comparison, very few variants initially classified as pathogenic or benign were reclassified as something else.

“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,” said Ross. “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.”

The study reflects the experience of just one laboratory and focuses exclusively on cancer tests. Despite these limitations, it shares some important information about the issues associated with VUS, wrote Wylie Burke, MD, PhD, professor of bioethics and humanities at the University of Washington, Seattle, in a related editorial. “Given the sheer number of gene variants that will be identified with increasing use of genomic testing, the problem posed by [VUS] is substantial,” Burke wrote.

“Prudence would dictate that genomic screening programs not report [VUS], but if so, screening programs need to consider whether they have a responsibility to promote and report reclassification,” she added. Public reporting of reclassification of variant pathogenicity may be one way to document the problem while solidifying trust and transparency in genetic testing, Burke suggested.

https://www.aacc.org/publications/cln/cln-stat/2018/november/15/the-case-for-reanalyzing-variant-calls