Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry

Abstract

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.

Figure 1.

Nonbenign variants (n = 1483) accrued per year, by class of gene. The volume of BRCA1/2 variants (hatched bars) fluctuated moderately from year to year. In contrast, the volume of non-BRCA1/2 variants (solid bars) went from negligible to very large in the final years of the study. We interpret the latter finding as consistent with the recent increase in use of multigene panel testing (1,11).

Figure 2.

Time to first reclassification of the variant, by initial classification. For ease of interpretation, this Kaplan-Meier plot illustrates follow-up of the 1483 variants through their first reclassification only. Variants are distinguished by their initial classification: likely benign (dotted line), likely pathogenic (dash-dot line), pathogenic (dashed line), variant of uncertain significance (solid line). Numbers of unreclassified variants remaining in follow-up are shown below the plot. As the plot indicates, variants initially classified as pathogenic were almost never reclassified. In contrast, the other three classes of variants were often reclassified, with a shared pattern of time to first reclassification that suggests that almost all nonpathogenic, nonbenign variants will be reclassified eventually. LB = likely benign; LP = likely pathogenic; P = pathogenic; VUS = variant of uncertain significance.

Figure 3.

Model-derived estimates of annual growth in rate of reclassification of BRCA1 variants, by ancestry. These panels illustrate two ways of plotting the ancestry-specific variation in reclassification of BRCA1/2 variants as reported in Table 2. For clarity, these plots use estimates for that model’s referent category, specifically nonpathogenic BRCA1 variants from females tested by Lab A. Estimates for BRCA2 or pathogenic variants, or those from males or Other Labs, can be obtained by applying the corresponding relative rates in Table 2 to these plots. In both, the x-axis corresponds to the calendar year when the variant was initially classified. A) In this plot, the reclassification rate in 1997 was set to 1.00 for all ancestries, ignoring the substantial initial variation among ancestries in favor of illustrating ancestry-specific patterns of change in reclassification rate over time. B) In contrast, here each ancestry’s estimated annual growth in reclassification rate was applied to its own baseline rate from 1997, relative to the reference category of non-Hispanic European (NHE). From this second plot, we conclude that, for variants from all minority ancestries except non-Chinese Asian and Hispanic, the rate of reclassification eventually equaled or surpassed the NHE rate.