Using species richness calculations to model the global profile of unsampled pathogenic variants: Examples fromBRCA1andBRCA2

Abstract

AbstractThere have been many surveys of genetic variation inBRCA1andBRCA2to identify variant prevalence and catalogue population specific variants, yet none have evaluated the magnitude of unobserved variation. We applied species richness estimation methods from ecology to estimate “variant richness” and determine how many germline pathogenicBRCA1/2variants have yet to be identified and the frequency of these missing variants in different populations. We also estimated the prevalence of germline pathogenicBRCA1/2variants and identified those expected to be most common. Data was obtained from a literature search including studies conducted globally that tested the entirety ofBRCA1/2for pathogenic variation. Across countries, 45% to 88% of variants were estimated to be missing, i.e., present in the population but not observed in study data. Estimated variant frequencies in each country showed a higher proportion of rare variants compared to recurrent variants. The median prevalence estimate ofBRCA1/2pathogenic variant carriers was 0.64%.BRCA1c.68_69del is likely the most recurrentBRCA1/2variant globally due to its estimated prevalence in India. Modeling variant richness using ecology methods may assist in evaluating clinical targeted assays by providing a picture of what is observed with estimates of what is still unknown.