Prospective Study of Cancer Genetic Variants

Variation in Rate of Reclassification by Ancestry

Thomas P. Slavin; Lily R. Van Tongeren; Carolyn E. Behrendt; Ilana Solomon; Christina Rybak; Bita Nehoray; Lili Kuzmich; Mariana Niell-Swiller; Kathleen R. Blazer; Shu Tao; Kai Yang; Julie O. Culver; Sharon Sand; Danielle Castillo; Josef Herzog; Stacy W. Gray; Jeffrey N. Weitzel;


J Natl Cancer Inst. 2018;110(10):1059-1066. 

In This Article

Abstract and Introduction


Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry.

Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing.

Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American.

Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.


Genetic testing for hereditary cancer susceptibility has dramatically improved delivery of precision cancer prevention or treatment to individuals who harbor pathogenic variants in cancer-associated genes. Increasingly, individuals undergoing a hereditary cancer risk assessment are tested with commercial multigene panels consisting of 25 genes or more.[1] Laboratories classify genetic variants along a continuum of clinical significance (ie, pathogenic, likely pathogenic, variant of uncertain significance [VUS], likely benign, or benign).[2] As genomic knowledge evolves, however, variants can be reclassified from one category to another, often with clinical implications for the recipient. Because time to reclassification is highly variable and can exceed a decade or more,[3] tested individuals often make health-related decisions based on initial rather than definitive interpretations of their genomic data.

Despite the fact that variant reclassification may have profound implications for patient care and medical decision-making, little is known about the factors associated with variant reclassification. One factor that may be important in variant reclassification is ancestry. When classifying or reclassifying variants, labs rely heavily on reference databases of human genetic variation. However, because persons of European descent continue to be disproportionately overrepresented within reference genetic databases,[4–6] individuals of non-European ancestry are more likely to receive uncertain test results.[7–9] Given potential ethnic disparities in the initial classification of genetic variants, we hypothesized that the rate of reclassification of nonbenign variants likewise differs by ancestry, independent of potential confounding factors such as time, gene, laboratory, and initial classification.

To address this hypothesis, we analyzed a prospective cohort of pathogenic, likely pathogenic, VUS, and likely benign variants identified during two decades of a tertiary care–based program for hereditary cancer risk assessment among an ethnically diverse population. Recognizing broad differences in the history and scale of efforts to research and reclassify variants of hereditary breast cancer genes (BRCA1/2) and other genes, we analyzed those two groups of variants separately. As secondary aims, we examined time to reclassification by initial classification and identified characteristics that distinguish reclassified variants that were upgraded.