Reclassification Strategies
Multiple approaches to VUS classification and reclassification exist, but no universally accepted standard or approach for determining if a variant is pathogenic or how a VUS should be reported or reclassified is available (Cheon et al., 2014). Some databases share data about variants, but a great deal of data about variants are proprietary. For example, Myriad Genetic Laboratories had a patent on BRCA1 and BRCA2 testing until 2013; consequently, the company has a large proprietary database of BRCA1 and BRCA2 data, which has enabled its reclassification of many VUSs in BRCA1 and BRCA2 (Cheon et al., 2014). The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has demonstrated how a collaborative effort to have a central repository for variant classification can be effective. InSiGHT examined variants in Lynch syndrome for the MLH1, MSH2, MSH6, and PMS2 genes, resulting in the evaluation of 2,360 variants and the reclassification of 605 variants (Thompson et al., 2014). The best solution would be to have a central repository for all data, but that is not yet a reality.
Multiple strategies are often combined and required to determine if a VUS is pathogenic or benign (Eggington et al., 2014; Millot et al., 2012; Moghadasi et al., 2013; Radice, De Summa, Caleca, & Tommasi, 2011; Rehm et al., 2013; Sijmons, Greenblatt, & Genuardi, 2013). Most laboratories use a variety of methods to reclassify a variant (see Figure 2). Reclassification is not universally carried out the same way across laboratories and agencies.
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Figure 2.
Selected Reclassification Techniques
Note. Based on information from Eggington et al., 2014; Millot et al., 2012; Moghadasi et al., 2013; Radice et al., 2011; Rehm et al., 2013; Sijmons et al., 2013.