Research Perspectives:

The effects of genomic germline variant reclassification on clinical cancer care

Thomas P. Slavin _, Sophia Manjarrez, Colin C. Pritchard, Stacy Gray and Jeffrey N. Weitzel

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Oncotarget. 2019; 10:417-423. https://doi.org/10.18632/oncotarget.26501

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Thomas P. Slavin1,2, Sophia Manjarrez1, Colin C. Pritchard3, Stacy Gray1,2 and Jeffrey N. Weitzel1,2

1 Department of Medical Oncology and Therapeutics Research, Division of Clinical Cancer Genomics, City of Hope, Duarte, CA, USA

2 Department of Population Sciences, City of Hope, Duarte, CA, USA

3 Department of Laboratory Medicine, University of Washington, Seattle, WA, USA

Correspondence to:

Thomas P. Slavin, email: [email protected]

Keywords: variant reclassification; BRCA1; BRCA2; genetic testing; hereditary cancer

Received: November 28, 2018    Accepted: December 04, 2018    Published: January 11, 2019


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.

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