Cascade Genetic Testing of Relatives for Hereditary Cancer Risk: Results of an Online Initiative

Abstract

In cascade testing, genetic testing for an identified familial pathogenic variant extends to disease-free relatives to allow genetically targeted disease prevention. We evaluated the results of an online initiative in which carriers of 1 of 30 cancer-associated genes, or their first-degree relatives, could offer low-cost testing to at-risk first-degree relatives. In the first year, 1101 applicants invited 2280 first-degree relatives to undergo genetic testing. Of invited relatives, 47.5% (95% confidence interval [CI] = 45.5 to 49.6%) underwent genetic testing, and 12.0% (95% CI = 9.2 to 14.8%) who tested positive continued the cascade by inviting additional relatives to test. Of tested relatives, 4.9% (95% CI = 3.8 to 6.1%) had a pathogenic variant in a different gene from the known familial one, and 16.8% (95% CI = 14.7 to 18.8%) had a variant of uncertain significance. These results suggest that an online, low-cost program is an effective approach to implementing cascade testing, and that up to 5% of the general population may carry a pathogenic variant in 1 of 30 cancer-associated genes.

Figure 1.

The family testing program. A) Flowchart of the application process. Positive results were available only after telephone-based genetic counseling, and posttest genetic counseling was also optionally available if the results were variant of uncertain significance or negative. B) Affected genes and uptake of testing. FDR = first-degree relative.

Figure 2.

Panel testing results of first-degree relatives of carriers. A) Overall results. B) Unexpected pathogenic variants.