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Referee Report: https://doi.org/10.21956/wellcomeopenres.17121.r37289, Gert Matthijs, Center for Human Genetics, KU Leuven, Leuven, Belgium, 12 Dec 2019, version 2, indexed

Referee Report: https://doi.org/10.21956/wellcomeopenres.16463.r34792, Christa L Martin, Erin Rooney Riggs, Heidi Rehm, Autism & Developmental Medicine Institute (ADMI), Geisinger Health System, Danville, PA, USA, 11 Mar 2019, version 1, 1 approved, 1 approved with reservations

Referee Comment: <b>Caroline Wright</b>; <i>Posted: 02 Dec 2019</i>; Wright and colleagues have written an open letter to address genomic variant sharing. It is a thorough and excellent accounting of the rationale for this type of data sharing and we commend the authors for taking the time to thoughtfully review and provide guidance on this important topic. <b><i>We thank the reviewer for their positive comments.</i></b> &nbsp; We are aware of at least one other “differing” opinion that was not represented here: the opinion that public data sharing highlights discordance in variant interpretation and is potentially confusing for clinical users ¹ ^, ². Our group believes that exposing discordant classifications between laboratories is actually a <i>benefit</i> to data sharing, allowing laboratories to see where they differ and work together towards concordance ³ ^, ⁴ ^, ⁵. <b><i>This is a good point and we agree with the reviewer. We have added a sentence about this into the manuscript with these additional references.</i></b> In the first section under “Recommendations” the first recommendation suggests only sharing “plausibly causal” genetic variants. We think this recommendation is insufficient and strongly encourage this guidance to include sharing of <i>all</i> variants that have been reviewed. The literature and databases are currently littered with false claims of causality/pathogenicity. It is critically important that we also share evidence on variants that are deemed benign or uncertain, or, at the case-level, deemed non-causal. Over three-quarters of ClinVar’s content is made up of variants classified as benign, likely benign, or variant of uncertain significance (VUS) and this data has been enormously useful to counter many of the false claims of pathogenicity from the literature. <b><i>See earlier comment about this and our concerns around linking a variant to a phenotype that it does not cause. </i></b> &nbsp; In addition, there is a bit of conflating of the concept of variant-level versus case-level interpretation and it would be useful to better separate these concepts in the paper. We have previously defined “variant-level” information as the aggregation of all evidence and observations to define the pathogenicity of a variant (i.e., its capacity to cause disease) ⁶. This may include evidence from a current case under investigation, but also takes into account all prior available data. However, whether a given variant is actually casual for the symptoms in a given patient is best called case-level interpretation and involves additional factors such as penetrance, a phenotype match with the relevant gene, and allelic information (e.g., recessive disease requires two alleles). <b><i>We have tried to clarify this throughout the text.</i></b> Related to this issue, we recommend in the section that outlines five specific data elements and references our prior publication ⁶, that items 2 and 4 be swapped to start with the variant level claim and then include the patient phenotype as part of the supporting evidence. This approach is more in line with variant-level data sharing and our referenced publication, which should be distinguished from case-level sharing, which is also important, but requires additional considerations as the authors have pointed out. Similarly, the variant claim (e.g., pathogenic, benign) should be asserted against a disease, not the patient’s clinical features, which should be left to the case-level interpretation step. We have made suggested edits below to data elements 3 and 4 to better clarify these points (additions in bold, deletions indicate by strikethrough): &nbsp; <i>“Specific data elements for sharing individual genetic variants have been outlined previously⁴² and include (see Table 1):</i> <i>1. a standardised genetic description of the variant(s), including Human Genome Variation Society (HGVS) nomenclature and genomic coordinates of the variant;</i> <i>2. the clinical significance and summary of evidence upon which that assertion was based; </i> <i>3. the <b>disease and</b> inheritance pattern of the disease (e.g. dominant/recessive) <b>upon which the clinical significance is asserted</b>;</i> <i>4. a standardised clinical description <b>of any of </b>the clinical features in the patient<b>(s)that are included as supporting observations for the variant assertion</b>, using appropriately controlled vocabulary/ ontology;and</i> <i>5. a cryptic link to the laboratory or clinical service that submitted the data (to enable further information to be requested and avoid data duplication).”</i> <b><i>We have made these changes.</i></b> Next, the authors state, “We recommend a cryptic link to the individual case-level data is maintained in a de-identified fashion via the laboratory or clinical service that submitted the data, that may obscure its geographical location by deposition via another platform, to enable clinical follow-up if needed.” We think this topic requires further consideration of the benefits and drawbacks of obscuring the submitter’s location. For most laboratories that perform a large volume of testing and receive samples from geographically diverse locations, it seems unnecessary to obscure the geographical location of the laboratory and data; indeed, the geographical location of the laboratory is easily discernible given that individual variants are attributed to specific laboratories in databases, such as ClinVar. ClinVar has operated with transparency to the submitter and their location without harm for several years now. To the contrary, it can be helpful to recognize the potential for data duplication, which is not uncommon. We would suggest a more nuanced discussion of this topic.&nbsp;For example, one may consider obscuring geographical location only in instances where the population is small or geographically isolated. <b><i>This is an interesting point, but a more nuanced discussion is outside the scope of this paper. We have changed the text to suggest that the “precise” geographic location should be obscured, but have not discussed it in further detail as this issue will vary between countries depending upon the catchment area of the testing laboratory.</i></b> &nbsp; Finally, it would be useful if the authors gave more concrete suggestions for where laboratories should submit their classified variants today. Do the authors support that direct submission to ClinVar is one recommended option? The authors describe both ClinVar and DECIPHER, but it is unclear what their recommendation would be. Given the momentum that ClinVar has achieved, it seems important that wherever the variant classifications are initially generated and stored, that they also be easily submitted to ClinVar. DECIPHER does have the advantage of a richer connection to case-level data. If DECIPHER took on a role as an additional site of primary variant deposition (not clear if it accepts individual submitted variant interpretations), we would assume the authors would agree that it would still be important for DECIPHER to facilitate submission to ClinVar on behalf of its users, in the same way that DECIPHER is able to fully consume ClinVar data. Would this be a second recommended option? More detail around any recommendations and/or future plans would likely be useful to readers. <b><i>We do not wish to prescribe where users should deposit their data, as many databases offer slightly different features. Instead, we support the federation of databases using systems such as MME, to ensure that data are not siloed. We have added a sentence about MME.</i></b> <b>Minor suggestions and edits: </b> In the abstract the authors state: “We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine.” We assume the authors mean a small number “per individual” but we read it as stating that each “source/laboratory” should only share a small amount of data, in general. We suggest deleting “a small number of” and saving the nuance of per individual issue for later in the paper. Alternatively, you could reword the statement to read: “We therefore recommend that widespread sharing of a small number of an individual’s genetic variants associated with limited clinical information should become standard practice in genomic medicine.” This same issue occurs in the second paragraph of the section “Finding a balance”. In the sentence “...sharing a tiny subset of..” we suggest adding “an individual’s” after “of”. <b><i>We have made these changes.</i></b> &nbsp; In the last sentence of the abstract the authors state “For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing…..”. We fear this could be implied as abandoning the core suggestion if one wants to also share case-level data and therefore we suggest clarifying by adding “this additional” so the sentence reads “...it may be more appropriate to use a controlled-access model for this additional data sharing…..” <b><i>We have made this change.</i></b> For the second Recommendation “A single genetic variant is not personally identifiable information; however, it is good practice to maintain a cryptic link to the laboratory or clinical service that shared the genetic data so that clinical follow-up remains possible should knowledge of the implications of a variant change.” We suggest adding “or to combine data to build evidence”. In our experience, many variants change classifications once labs bring their evidence/observations together, but a source for contact is needed to communicate and bring the data together. <b><i>We have made this change.</i></b> &nbsp; Another good example of patient benefit, and avoidance of harm, from data sharing is Grant et al, referenced below, in case you would like to cite ⁷. <b><i>We have added this reference.</i></b> The authors state: “....US-based ClinVar is perhaps the leading genetic variant deposition database…….but most variants have only very limited or no clinical information and no supporting evidence associated with them.” This statement is not completely accurate. While it is true that most entries do not contain patient data, the majority (62%) of the &gt;170,000 pathogenic/likely pathogenic variants have supporting evidence, either as a written evidence summary and/or PubMed citations. <b><i>Thank you, we have updated the text with this information.</i></b>

Grant Information: This work was supported by the Wellcome Transforming Genomic Medicine Initiative [200990]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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