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Variant reclassifications ‘common’ after hereditary cancer genetic testing

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October 24, 2018

About 25% of genetic variants of uncertain significance detected in testing for hereditary cancer risk were later reclassified as benign or pathogenic, according to a retrospective study that assessed 10 years of data from a single institution.

“Genetic testing results play a substantial role in medical management of hereditary cancers and may inform screening, surgery recommendations and treatment decisions,” Theodora Ross, MD, PhD, professor of internal medicine at UT Southwestern Medical Center, and colleagues wrote. “Given the clinical implications of genetic testing, accurate and timely variant classification is increasingly important for appropriate long-term patient care. It is, therefore, critical that new information for variants in cancer risk genes be reviewed by testing laboratories in order to evaluate whether reclassification is appropriate.”

To analyze reclassification of genetic variants, Ross and colleagues reviewed charts for 1.45 million individuals (median age, 49 years; 95.6% women) who underwent genetic testing patients at UT Southwestern Medical Center From 2006 to 2016. More than half (56.6%) had a personal history of cancer.

Researchers classified variants as benign, likely benign, variant of uncertain significance, likely pathogenic or pathogenic.

The analysis included 1.67 million initial tests and 59,955 reports that were amended due to reclassification of at least one variant.

Of 44,777 unique variants identified in the initial tests, 6.4% were reclassified over the course of the study. When researchers took into consideration the fact that most variants occurred in multiple individuals, they calculated that 24.9% of all reported variants of uncertain significance across individuals and tests were reclassified.

When evaluating unique variants, researchers found reclassification occurred rarely among those initially identified as pathogenic or likely pathogenic (0.7%; n = 61 of 9,112) or benign or likely benign (0.2%; n = 15 of 8,995).

Of the 26,670 unique variants initially classified as having uncertain significance, 7.7% were reclassified. Most of these (91.2%) were downgraded to benign or likely benign after a median of 1.17 years. The remaining 8.7% of variants with initial uncertain significance were upgraded to pathogenic or likely pathogenic variants after a median of 1.86 years.

The researchers anticipate that as testing becomes more common and encompasses more genes, the number of people with genetic variants that are upgraded from uncertain significance to pathogenic will continue to rise. “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,” Ross said in a press release. “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 limitations of the study included the observational, single-institutional study design and the nonrepresentative study population.

In an accompanying editorial, Wylie Burke, MD, PhD, professor in department of bioethics and humanities at University of Washington, highlighted how reclassification of genetic variants could impact clinicians.

“Genomic testing is a useful tool in oncology and is increasingly used in other areas of clinical medicine, notably cardiology and neurology,” she wrote. “But it is a tool that must be used with care. Test results must be interpreted in the context of other clinical information, and uncertainties must be communicated to patients. Clinicians should anticipate variants of unknown significance as a frequent outcome of testing and counsel patients accordingly.” – by Cassie Homer

Disclosures: Ross and Burke report no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

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