The Study: Ah, those BRCA variants of uncertain significance. They can be incredibly frustrating. So much so these patients end up with higher rates of bilateral mastectomies. If only we were more certain of their significance. In this study, saturation genome editing was used to introduce almost every possible single-nucleotide variant in the most important functional domains of the BRCA1 gene. Because with CRISPR capability, why not? The effects of each variant on the functionality of the BRCA1 protein were then scored. As you can imagine, the vast majority of the variants and their effects have never been reported in humans. But, among variants actually found in people, the sensitivity and specificity for pathogenicity were over 95%. This study is a very big deal. As the authors point out, the biggest current limitation in genomic data is knowing what the heck to do with it. And we’ll likely never accumulate enough patient-level information to remedy this. Instead, they argue that the time is right for implementing functional genomic classification scores—with BRCA testing being a prime target. With this type of testing, variants can magically go from “uncertain significance” to “likely pathogenic” or “likely benign.” Itching to know the functional significance of a variant? Check out Supplementary Table 1 for the full file of every variant’s score.
Bottom Line: Saturation genome editing and functional scoring can help give significance to genomic variants of uncertain significance. | Findlay, Nature 2018