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


This study of an ethnically diverse cohort of nonbenign variants followed for up to two decades reveals for the first time that, independent of covariates, the rate of variant reclassification varies by ancestry. Overall, current findings suggest a "catching up" in the reclassification of variants from minority ancestries after an excess in uncertain classifications (VUS) relative to non-Hispanic European tests. This pattern was likely facilitated by the availability of large population databases such as the National Heart, Lung, and Blood Institute Exome Sequencing Project and 1000 Genomes, followed by the more ethnically diverse Exome Aggregation Consortium (ExAC) database.[4,12,13] Further, a "catching up" of reclassification would be consistent with a previous report that the frequency of VUS as a percentage of all variant classifications declined during the decades we studied,[14] most steeply among African, Asian, Hispanic, and Middle Eastern ancestries.

The current study also reports that the percentage of reclassifications that are net upgrades is low (less than half the 20% reported by an earlier study limited to BRCA1/2 variants).[15] Moreover, this percentage has declined steeply in recent years. Importantly for clinical care and genetic counseling, the latter finding argues against the view that VUS are commonly upgraded to pathogenic or likely pathogenic status, an assumption that may lead individuals who receive these results to undergo unnecessary procedures (ie, bilateral mastectomy).[16] We identify initial classification, sex, and calendar year of testing (but not ancestry, laboratory, or splice site mutation)[15] as risk factors for a reclassification being a net upgrade.

Findings incidental to our primary hypothesis include two unanticipated associations with sex. Specifically, BRCA1/2 variants from male participants appear more likely to undergo reclassification. Also, regardless of gene, reclassified variants from male participants appear more likely to have undergone a net upgrade in pathogenicity. Neither of these associations with sex can be explained by any of the variant characteristics we studied. Possibly, these associations may be related to males' greater reluctance to seek medical care generally.[17] We speculate that, to present for cancer genetic risk assessment, males may tend to require a more compelling family history of cancer than females do. In turn, a more compelling family history may promote initiation and completion of the research necessary to issue a reclassification and may also be associated with genetic variants of greater pathogenicity. In any case, current incidental associations with sex should be regarded as preliminary until confirmed by separate studies.

The current longitudinal analysis of time to reclassification suggests that, except for pathogenic variants, most nonbenign test results will ultimately be reclassified. For that reason, persons undergoing genetic testing should be encouraged to provide (and update) contact information to the provider ordering the test, so that they may be informed of reclassifications as they are issued. Current findings also indicate that the various classes of nonpathogenic variants (likely pathogenic, likely benign, VUS) are equally likely to undergo reclassification, while reclassifications of likely pathogenic variants are more likely than VUS reclassifications to be net upgrades. The latter finding supports the current clinical practice of treating likely pathogenic variants as similar to pathogenic variants.[1]

To our knowledge, only a limited description of time to variant reclassification has been published previously.[3] That retrospective study (n = 107 women whose BRCA1/2 variants were exclusively VUS) did not provide median time to reclassification or rate per years of observation. In contrast, our prospective study has presented time to first reclassification by classification and modeled rate of reclassification within ancestry groups over time while controlling potential confounding factors. Moreover, our large sample was intended to be representative of contemporary clinical practice and thus accepted variants 1) from genes other than BRCA1/2, 2) with classifications not restricted to VUS, 3) from males as well as females, and 4) regardless of whether the participant carried a pathogenic BRCA1/2 variant.

One methodological challenge inherent in research into reclassification of genetic variants is that, due to lack of specific regulations, internal proprietary data, and varying methodologies, commercial genetic laboratories do not follow a common protocol for issuing reclassifications. Some laboratories (ie, Lab A) have active, system-based approaches that generate reclassifications. Alternatively, laboratories may issue reclassifications only sporadically, for example, when new clinical or empirical evidence is brought forward by a health care provider or a laboratory director. Over time, laboratories may shift between sporadic and active reclassification programs without notice. Recognizing the complex heterogeneity in reclassification programs, we included all commercial laboratories used during the study period but took steps to prevent laboratory differences from confounding our investigation. Specifically, we took into account within-laboratory correlation, distinguished the most active laboratory from all others, and considered BRCA1/2 and non-BRCA1/2 variants separately.

Another methodological challenge inherent in our study relates to the categorization of ancestry from self-report. To avoid oversimplifying ancestry, we recognized diversity within the "Asian" category, replacing it with categories of Chinese, Middle Eastern, and other Asian ancestry. On the other hand, clarity required us to identify systematically one ancestry per participant when several were reported. Mixed ancestry was reported by a minority of our participants, chiefly, as expected from studies of admixture, those with Ashkenazi, African, or Native American ancestry.[18] In the future, studies of reclassification rates might benefit from analyzing ancestry using ethnic percentages or germline DNA-based categorization.

Our study findings are specific to the era and genes that we studied. In the future, reference databases will become more ethnically diverse,[4,6] routine genetic testing will include more genes, and new methodologies will become prevalent, such as polygenic risk scoring using single nucleotide polymorphisms, whole-exome and -genome sequencing, and secondary germline findings from tumor-based testing. As a result, the ancestry-based associations with reclassification that we have observed are likely to evolve.

In conclusion, the current study investigates the role of ancestry in variant reclassification during two decades of clinical practice. Our findings demonstrate that independently of laboratory and initial classification, the rate at which a nonbenign cancer genetic variant is reclassified varies by ancestry in ways that depend on gene (BRCA1/2 vs others) and, when observation spans more than a few years, on the year when a genetic variant was classified.