Patients With a Genetic Variant of Unknown Significance
Patients With a Genetic Variant of Unknown Significance
Several possibilities follow the reporting of genetic testing results, including a known pathogenic or deleterious mutation, a VUS, or a negative report (see Table 1). A negative test result does not necessarily indicate that the patient has no increased risk for developing cancer. A true negative occurs when a known pathogenic mutation is already present in the family. If the patient tests negative, he or she has not inherited the elevated risk but still has the population risk for developing cancer. When a negative test result occurs in the first person tested in the family (no prior known mutation exists), no pathogenic mutation has been detected in that person, and the result is noninformative. The individual may have benign polymorphisms that most likely will not be reported. Alternatively, he or she may not have a germline mutation or may have a germline mutation for which testing is not available. In addition, the cause of cancer could be attributed to another gene or hereditary syndrome.
Next-generation sequencing has resulted in the detection of pathogenic mutations in less common genes and has increased the number of VUSs found because more genes are included in the analyses. Less is known about some of the newer genes (e.g., their clinical implications, whether genetic changes within newer genes are pathogenic). For example, Myriad Genetic Laboratories reported that the VUS rate decreased from 12.8% of all BRCA1 and BRCA2 test results in 2002 to 2.1% of all test results in 2013, and credited the decline to more being learned about the genes and the existence of a larger database (Eggington et al., 2014). In a study of 175 patients who underwent next-generation panel testing, 428 VUSs were identified in 39 different genes, resulting in an average of 2.1 VUSs per patient (Kurian et al., 2014). Rates of VUSs in next-generation panels may approach 20% (Selkirk et al., 2014). Variant rates may be higher in minority populations because they are not represented as well in databases (Murray, Cerrato, Bennett, & Jarvik, 2011). Many variants are reclassified as more information becomes available, but, in many cases, this can take years (Cheon, Mozersky, & Cook-Deegan, 2014).
Scope of the Problem
Several possibilities follow the reporting of genetic testing results, including a known pathogenic or deleterious mutation, a VUS, or a negative report (see Table 1). A negative test result does not necessarily indicate that the patient has no increased risk for developing cancer. A true negative occurs when a known pathogenic mutation is already present in the family. If the patient tests negative, he or she has not inherited the elevated risk but still has the population risk for developing cancer. When a negative test result occurs in the first person tested in the family (no prior known mutation exists), no pathogenic mutation has been detected in that person, and the result is noninformative. The individual may have benign polymorphisms that most likely will not be reported. Alternatively, he or she may not have a germline mutation or may have a germline mutation for which testing is not available. In addition, the cause of cancer could be attributed to another gene or hereditary syndrome.
Next-generation sequencing has resulted in the detection of pathogenic mutations in less common genes and has increased the number of VUSs found because more genes are included in the analyses. Less is known about some of the newer genes (e.g., their clinical implications, whether genetic changes within newer genes are pathogenic). For example, Myriad Genetic Laboratories reported that the VUS rate decreased from 12.8% of all BRCA1 and BRCA2 test results in 2002 to 2.1% of all test results in 2013, and credited the decline to more being learned about the genes and the existence of a larger database (Eggington et al., 2014). In a study of 175 patients who underwent next-generation panel testing, 428 VUSs were identified in 39 different genes, resulting in an average of 2.1 VUSs per patient (Kurian et al., 2014). Rates of VUSs in next-generation panels may approach 20% (Selkirk et al., 2014). Variant rates may be higher in minority populations because they are not represented as well in databases (Murray, Cerrato, Bennett, & Jarvik, 2011). Many variants are reclassified as more information becomes available, but, in many cases, this can take years (Cheon, Mozersky, & Cook-Deegan, 2014).
