One-Fourth of Myriad’s Variants of Unknown Significance Reclassified Over 10 Years

Variant reclassification following hereditary cancer genetic testing is common, according to a study published by Myriad Genetics (Salt Lake City) Sept. 25 in the Journal of the American Medical Association. Over a 10-year period, one-fourth of all reported variants of uncertain significance were reclassified, including downgrading of 91 percent to benign or likely benign and upgrading of nine percent to pathogenic or likely pathogenic.

“The implications of this study are three-pronged,” said senior study author Theodora Ross, M.D., Ph.D., in a statement. “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.”

Researchers retrospectively analyzed results of individuals (95.6 percent women) who had genetic testing (initial single-syndrome test, pan-cancer panel, or both) conducted at Myriad Genetics from 2006 through 2016. Variants were classified as benign, likely benign, variants of uncertain significance (VUS), likely pathogenic, or pathogenic. An automated system analyzed new evidence from published literature and methods specific to the testing laboratory daily. When variant reclassification was appropriate, the testing laboratory sent an amended report indicating the new classification to the clinician. Additionally, a retrospective chart review was conducted for a subset of patients (n = 8,427) seen at the University of Texas Southwestern Medical Center (UTSW).

Over the study period, there were 44,777 unique variants detected and observed a total of 6.22 million times. In the UTSW subset, 3,158 unique variants were detected a total of 187,033 times. Overall, 5.4 percent (n = 90,052) of all test reports were positive (with at least one pathogenic or likely pathogenic variant) and 5.8 percent (n = 96,684) were negative (no pathogenic or likely pathogenic variant), but with one or more VUS. In the UTSW subset, 9,493 initial test reports were issued over the study period, of which 6.9 percent (n = 658) had a positive test result and 9.4 percent (n = 897) had a negative test result with at least one VUS.

Of the 1.67 million initial tests, 59,955 reports were amended over the study period due to variant reclassification, with 6.4 percent of 44,777 unique variants reclassified. Reclassification (upgrades or downgrades) to a different clinical category was rare among unique variants initially classified as pathogenic/likely pathogenic (61 of 9,112) or benign/likely benign (15 of 8,995).

Of the 26,670 unique VUS that were initially detected (seen 184,327 times), 7.7 percent were reclassified—with the vast majority (91.2 percent) downgraded to less severe classifications and 8.7 percent upgraded to more severe classifications. (either pathogenic or likely pathogenic variants). This yielded reclassification of  24.9 percent (46,890 of 184,327) of all reported VUS.

In the UTSW subset, 9.1% (287 of 3,158) of unique variants were reclassified, including 11 VUS that were upgraded to pathogenic or likely pathogenic. No known interim cancers were diagnosed in the patients prior to reclassification. However, in three cases, upgrades of VUS enabled patients to qualify for new treatments.

“The number of individuals with variants of uncertain significance will likely continue to rise nationally as (1) genetic awareness increases leading to more individuals being tested, (2) disease gene panel adoption rises, (3) the number of genes included in testing increases, and (4) the cost of genetic testing decreases,” write the authors led by Jacqueline Mersch, from University of Texas Southwestern Medical Center in Dallas. “As such, the absolute number of individuals with variants of uncertain significance that are later upgraded to pathogenic will continue to rise.”

The median time to the amended report due to variant reclassification was 1.10 years overall, and 1.06 years in the UTSW subset.

“Collectively, this highlights the continued importance of an efficient and accurate reclassification program to ensure up-to-date clinical management to reduce hereditary cancer risk,” warn the authors.

Takeaway: Reclassification of VUS is common and laboratories need to ensure they have a system in place to re-evaluate new evidence and to report updated findings to clinicians and patients.