Mersch J, et al. - As variant reclassification is a critical part of hereditary cancer genetic testing, researchers investigated the frequency and types of variant reclassifications for which amended reports are issued as part of hereditary cancer genetic testing. In this retrospective cohort study of 1.45 million individuals and 1.67 million initial tests, variant reclassification led to issuing of 59,955 amended reports. Among variants initially classified as uncertain significance, reclassification of 7.7% was done; 91.2% of these were downgraded to less severe classifications and 8.7% were upgraded to more severe classifications.

Methods

• Researchers conducted a retrospective cohort study assessing patients who had genetic testing between 2006 and 2016 at a single commercial laboratory.
• They classified the variants as benign, likely benign, variant of uncertain significance, likely pathogenic, or pathogenic.
• For patients from the University of Texas Southwestern (UTSW) Medical Center, they conducted retrospective chart reviews.
• Frequency of and time to amended reports and frequency and types of variant reclassification were assessed as the main outcomes and measures.

Results

• A total of 1.45 million individuals (median [interquartile range] age at testing, 49 years [40.69-58.31 years], 95.6% women) underwent genetic testing from 2006 through 2018; among these, 56.6% (n = 821,724) had a personal history of cancer.
• Data indicated that a total of 1.67 million initial tests were performed; variant reclassification led to issuing of 59,955 amended reports.
• Overall, reclassification was done for 6.4% (2,868 of 44,777) of unique variants.
• Unique variants initially classified as pathogenic or likely pathogenic (0.7%, 61 of 9,112) or benign or likely benign (0.2%, 15 of 8,995) were rarely reclassified to a different clinical category.
• However, 7.7% (2,048 of 26,670) of unique variants of uncertain significance were reclassified: 91.2% (1,867 of 2,048) were downgraded to benign or likely benign (median time to amended report, 1.17 years), 8.7% (178 of 2,048) were upgraded to pathogenic or likely pathogenic variants (median time to amended report, 1.86 years).
• Reclassification of 24.9% (46,890 of 184,327) of all reported variants of uncertain significance was done, as most variants were observed in more than one individual.