The effects of genomic germline variant reclassification on clinical cancer care

The last two decades have provided an astounding amount of novel information about the human genome. Translating germline genomic data into clinically actionable findings is reliant on the annotation and laboratory classification of specific variants. Variant classification helps providers and patients determine if genomic findings can inform clinical management. In germline hereditary cancer predisposition testing, variants of uncertain significance (VUS) are routinely misunderstood. By definition, they cannot be classified by the testing laboratory as either problematic mutations or benign variants. Many VUS undergo category reclassifications over time (from months to years after initial classification) as more information is known about normal human genomic diversity, especially among underrepresented minority populations. When VUS are reclassified, it has been shown that they are often downgraded. Likewise, some variants originally thought to be actionable mutations are downgraded to VUS or benign variants. Rarely but importantly, VUS may be reclassified in a manner that increases their initial clinical significance. Here, we discuss the insights gained from the study of variant reclassification. We provide a case series to highlight the potential impact that variant reclassifications can have on individual and family cancer management, risk counseling, and screening.