Central to Watts and Newson’s argument in their seminal paper ‘ Is there a duty to routinely reinterpret genomic variant classifications? ’ is that diagnostic laboratories are not morally obligated to actively reinterpret variants of uncertain significance (VUS) due to the superior outcomes offered by next-generation sequencing (NGS) compared with traditional methods.1 NGS technologies can identify, analyse and interpret millions of genetic variations at once. For example, ‘the use of conventional molecular assays in clinical contexts could require doing a lot (...) of assays for various mutations. Using these different assays, more tissue may be required. These targets can accurately be questioned using NGS technology in a single test.’2 If NGS-based genomic sequencing is reliable and its output outweighs the potential harm of uncertainties, then, it is plausible to say that those test providers cannot incur a moral duty to actively reinterpret VUS because there won’t be any need to do so.1 Despite its seeming reliability, diagnostic laboratories face enormous challenges in implementing NGS-based …. (shrink)

The results of tests carried out using next-generation genomic sequencing (NGS) possess a peculiar and perhaps unique ‘diagnostic durability’. Unlike most other forms of testing, if genomic results or data are stored over time, then it remains possible to interrogate that information indefinitely, without having to retest the patient. Another peculiar property of genomic results is that their interpretations are subject to change within relatively short time frames. For instance, a genomic variant that is of uncertain significance (VUS) at the (...) time of testing may shortly afterwards come to be understood as pathogenic (P) or benign (B). Moreover, variant classifications might be downgraded from likely pathogenic to VUS or B, or regraded from B to VUS. These two properties of genomic testing have important implications for the responsible implementation of genomic testing in healthcare. One of these is that they prompt the question whether diagnostic laboratories are morally required to routinely reinterpret their genomic variant classifications and reissue patient reports in the case of materially relevant changes. We take up this question in our paper, in which we argue against the existence of any general duty to reinterpret genomic variant classifications (as had been argued for by Appelbaum et al 1). Still, we maintain that a restricted duty to reinterpret ought to be recognised.2 We thank the authors of the commentaries on our paper for their attention to our argument and for their thoughtful responses to (and expansions of) our position. Oerlemans et al address …. (shrink)

In their article on the limited duty to reinterpret genetic variants, Watts and Newson argue that clinical labs are not morally obligated to conduct routine reinterpretation despite its potential clinical and personal value.1 We endorse the authors’ argument for a circumscribed duty to reclassify genomic variants in certain cases, including to promote diagnostic equity for racial and ethnic minority populations that have been historically excluded from and exploited by genomic research and medicine. However, given the history and resilience of scientific (...) racism, the use of socially constructed racial and ethnic categories to enhance diagnostic equity raises several ethical and practical challenges. In the short term, using socially constructed racial and ethnic categories to identify patients for variant reclassification is a practical approach for addressing concerns of diagnostic equity. In contrast, diagnostic accuracy depends on patients’ genetic similarity to reference genomes, rather than their socially determined race or ethnicity.2 Thus, in the long term, securing both diagnostic equity and diagnostic accuracy through targeted variant reclassification will require a shift away from relying on race and ethnicity and towards assessing genetic similarity. Critically, the identification of patients for genomic variant reclassification using socially constructed race or ethnicity runs the risk of perpetuating the harmful …. (shrink)

While Gabriel Watts and Ainsley Newson argue that diagnostic laboratories do not have a general duty to routinely reinterpret genomic variant classifications, they do formulate several restricted duties to actively reinterpret specific types of classifications.1 They place these duties with laboratories, acknowledging that they are setting aside any responsibilities that might arise for clinicians. Here, we will discuss the implications of this obligation for clinicians and the moral tension it may confront them with. We focus in particular on the consequences (...) of the proposed moral obligation to actively reinterpret variant classifications that carry a higher risk of being false positives. Such reclassification is likely to result in ‘downgrades’: previously pathogenic variants (pathogenic/likely pathogenic, P/LP) reclassified to benign (likely benign/benign, LB/B) or uncertain variants (variant of uncertain significance, VUS). Any laboratory policy to actively reinterpret (specific sets of) classifications will confront the clinician with the question whether the person tested should be recontacted on a reinterpretation of previously reported results. As others have pointed out, recontacting in general comes with challenges, since patients may not want to be recontacted or have forgotten about their genetic test.2 3 Recontacting in case of a downgrade, however, is particularly impactful. Previous studies on the psychosocial impact of reclassification on patients …. (shrink)