Abstract
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.
Highlights
Variants identified through genetic testing must be classified according to their clinical significance
Variants in the pathogenic and likely pathogenic categories are treated as clinically actionable variants that could impact counseling and clinical care, whereas variants in the benign, likely benign, and variant of uncertain significance (VUS) categories are treated as clinically non-actionable (Figure 1) [2, 3]
Our findings showed that for non-benign variants in cancer-related genes, the rate of reclassification varied by ancestry and in ways that differed between BRCA1/2 and other genes [2]
Summary
Variants identified through genetic testing must be classified according to their clinical significance. Variants are frequently classified using guidelines jointly established by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology [1]. The ACMG guidelines classify variants in one of five tiers, from lowest to highest pathogenicity: benign, likely benign, variant of uncertain significance (VUS), likely pathogenic, and pathogenic. Variants in the pathogenic and likely pathogenic categories are treated as clinically actionable variants that could impact counseling and clinical care, whereas variants in the benign, likely benign, and VUS categories are treated as clinically non-actionable (Figure 1) [2, 3]. Variants are frequently reclassified and usually downgraded over time We recently reported the rates of variant reclassification by ancestry in individuals undergoing www.oncotarget.com
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