Results of germline genetic testing generally yield three types of test results: Deleterious (positive), Negative (no mutation detected), and Variant of Uncertain Significance (VUS). As more genes are tested, the chance for a positive result goes up, as does the chance of receiving a VUS result.1 VUS results tell us that it remains uncertain whether the test result is positive or negative. A recently published study demonstrated that most VUS results are downgraded to negative over time.2 Specifically, of more than 25,000 VUS results reported through a single testing laboratory, about a quarter were reclassified over time, of which over 90% were downgraded to negative (benign or likely benign). Information from this study is important when counseling patients with VUS results, informing them that most VUS results that are reclassified are downgraded, and explaining that VUS results are generally not used to direct medical care. On the topic of interpretation of genetic test results, another paper reported on a novel method to better classify BRCA1 mutations as positive or negative, through tracking how cells with specific BRCA1 changes, growing in lab dishes, respond.3 These types of efforts are important to better classify gene changes identified through genetic testing, and hopefully will serve to reduce the number of VUS results received by patients in the future. Finally, as knowledge expands, it becomes more important to make interpretation of genetic test information widely available for it to be maximally used to improve patient care. To that effect, a recent report outlined a global resource that includes data on more than 20,000 unique BRCA1 and BRCA2 variants, called the “BRCA Exchange”.4 Over 6,100 variants in this database have been classified by an expert panel, and approximately 3,700 are established to be positive (i.e., they raise the risk for cancer). This dataset was set up to pull in information from existing clinical databases, including the Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database, as well as other databases and data worldwide. It has a single-point-of-access website (https://brcaexchange.org/) and serves to demonstrate that this type of widespread data sharing across multiple entities is possible for other inherited cancer genes and genes associated with other diseases.
1Kurian AW, et al. JAMA. 2018 Aug 1. PMID: 29801090.
2Mersch J, et al. JAMA. 2018 Sept 25. PMID: 30264118.
3Findlay GM, et al. Nature. 2018 Oct. PMID: 30209399.
4Cline MS, et al. PLoS Genet. 2018 Dec 26. PMID: 30586411.