The impact of variant classification on the clinical management of hereditary cancer syndromes.

Purpose: The reclassification of genetic variants poses a significant challenge for laboratories and clinicians. Variant review has resulted in the reclassification of variants of unknown significance as well as the reclassification of previously established pathogenic and likely pathogenic variants. These reclassifications have the potential to alter the clinical management of patients with hereditary cancer syndromes.

Methods: Results were reviewed for 1694 patients seen for hereditary cancer evaluation between August 2012 and May 2017 to determine the frequency and types of variant reclassification. Patients with reclassifications with high potential for impact were monitored for alterations in organ surveillance, prophylactic surgery, and cascade testing.

Results: One hundred forty-two variants were reclassified representing 124/1694 (7.3%) patients; 11.3% of reclassifications (16/142) had a high potential for clinical impact with 94% (15/16) altering clinical management of patients with 56% (9/16) changing multiple areas of management.

Conclusion: While reclassifications are rare, the impact on clinical management is profound. In many cases, patients with downgraded pathogenic/likely pathogenic variants had years of unnecessary organ surveillance and underwent unneeded surgical intervention. In addition, cascade testing misidentified those at risk for developing cancers, thereby altering the management across generations. The frequency and types of alterations to clinical management highlight the need for timely variant reclassification.