Challenges of variant reinterpretation: Opinions of stakeholders and need for guidelines

Abstract

Purpose: The knowledge used to classify genetic variants is continually evolving, and the classification can change on the basis of newly available data. Although up-to-date variant classification is essential for clinical management, reproductive planning, and identifying at-risk family members, there is no consistent practice across laboratories or clinicians on how or under what circumstances to perform variant reinterpretation.

Methods: We conducted exploratory focus groups (N = 142) and surveys (N = 1753) with stakeholders involved in the process of variant reinterpretation (laboratory directors, clinical geneticists, genetic counselors, nongenetic providers, and patients/parents) to assess opinions on key issues, including initiation of reinterpretation, variants to report, termination of the responsibility to reinterpret, and concerns about consent, cost, and liability.

Results: Stakeholders widely agreed that there should be no fixed termination point to the responsibility to reinterpret a previously reported genetic variant. There were significant concerns about liability and lack of agreement about many logistical aspects of variant reinterpretation.

Conclusion: Our findings suggest a need to (1) develop consensus and (2) create transparency and awareness about the roles and responsibilities of parties involved in variant reinterpretation. These data provide a foundation for developing guidelines on variant reinterpretation that can aid in the development of a low-cost, scalable, and accessible approach.

Keywords: Genetic testing; Liability; Variant of uncertain significance; Variant reclassification; Variant reinterpretation.

Figure 1.. Initiation of reinterpretation.

Responses to a multiple-choice question, “Who should initiate reinterpretation? Who should be the primary party to decide that reinterpretation should be done to see if there is new information that may change the results of the initial genetic testing?” Comparison of the choice of laboratory to all other options showed an overall p-value of <.0001 (chi-square analysis). Clinical and laboratory genetic providers selected laboratory more frequently than the other groups (59% and 39% respectively, chi-square analysis, pairwise comparison with laboratory as the reference compared to each other and to patients/parents, p-value<.0001). The choice of laboratory was less common among non-genetic providers (24%, chi-square analysis, pairwise comparison with laboratory as the reference for non-genetic providers compared to clinical genetic providers and to patients/parents, p-value <.0001) and patients/parents (11%).

Figure 2.. Consent for reinterpretation.

(a) Responses to the question, “Should consent be required prior to reinterpretation?” Pairwise comparisons between the patients/parents compared to clinical genetic providers or laboratory genetic providers AND between the non-genetic providers compared to clinical genetic providers or laboratory genetic providers all had a p-value of <.0001 (chi-square analysis). (b) Response from those who responded yes (n=692, 39% of the total sample) to the multiple-choice question of “At what point should consent for reinterpretation be obtained?” The option of “other” was available but was removed from the figure.

Figure 3.. Duration of responsibility for reinterpretation.

(a) Responses to the question, “Should there be a point after a variant is reported when a lab should no longer be expected to reinterpret it?” While majority of respondents in all groups endorsed no end to a laboratory’s responsibility to reinterpret a previously reported variant, non-genetic providers (62%) were less frequent in this response than patients/parents and clinical genetic providers (80% and 85% respectively, chi-square analysis, pairwise comparison for non-genetic providers compared to clinical genetic providers and patients/parents, p-value <.0001). (b) Response from those who responded yes (n=385, 22% of the total sample) to the select all that apply question “What should that point be?”

Figure 4.. Liability for reinterpretation and recontact.

The black line marks the point of neutrality, where everything to the right indicates concern and everything to the left indicates neutrality or lack of concern. (a) Responses to the multiple-choice question, “How concerned or unconcerned would you be about legal liability if you had a duty to decide when reinterpretation of a patient’s genetic testing should be done?” (b) Responses to the multiple-choice question, “How concerned or unconcerned would you be about legal liability if you or your lab had a duty to recontact patients with reinterpreted results from their genetic testing?” For concern about recontact, we compared responses that expressed some level of concern to all other responses. For pairwise comparisons between the laboratory genetic providers compared to clinical genetic providers or non-genetic providers, the p-value was <.0001 (chi-square analysis).