Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists

Summary

Advances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1–5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible.

Multiplex assays of variant effects provide data for thousands of genetic variations, but robust clinical validation remains a barrier to clinical adoption. This was reflected in our November 2024 survey of UK NHS clinical scientists; their key recommendation was for clinical validation to be performed by a trusted central body.

Introduction

Rapid advances in high-throughput molecular and bioinformatic pipelines for genomic sequencing have shifted the bottleneck in diagnostic genetic testing to the clinical interpretation and classification of detected variants. Upon encountering a new, rare variant in clinical testing, population-level, case-control, segregation, and phenotype-related data from patients with the disease are frequently insufficient to enable robust classification as pathogenic or benign. Thus, this may result in classification as a variant of uncertain significance (VUS), a problem exacerbated in patients of non-European descent on account of smaller available population-level datasets.^1,2,3 Assays of variant impact on gene function provide an attractive alternative information source for differentiating which variants are deleterious and which are neutral with respect to function. Historically, functional assays have been low throughput, typically only reporting on a handful of repeatedly observed variants. Through concurrent advances in high-throughput sequencing and gene editing technologies, so-called multiplex assays of variant effect (MAVEs) can provide systematically generated data for many thousands of variants, enabling “pre-annotation” of (nearly) all variants that might ever be observed clinically.^4,5

Robust validation of the assay across the variant types deemed causative to the corresponding phenotype is critical to clinical applications for variant interpretation of data from MAVEs or any functional assay. For genes where disease is conferred through loss of function, this usually comprises analyzing the separation of assay readouts between synonymous and nonsense variants; this both validates the performance of the assay in predicting loss of function and allows calibration of thresholds for the designation of impact (or not) on function. However, under the 2015 (v.3) American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) variant classification framework, truncating and synonymous variants are less likely to be reliant on novel functional data to attain definitive classifications of (likely) pathogenic or benign.⁶ Rare missense variants (which are in aggregate quite frequent) are more commonly problematic for confident classification as pathogenic or benign. Hence, for these variants, it is important that the assay has been validated for its ability to distinguish between known benign and pathogenic missense variants. Methodology quantifying concordance of assay calls against variant truth sets (previously classified benign and pathogenic variants) and subsequently producing an assay-level “evidence strength” (as a log likelihood ratio) under the relevant ACMG/AMP codes for pathogenicity (PS3) and benignity (BS3) was approved by the ClinGen Sequence Variant Interpretation (SVI) Functional Working Group (WG) and published in 2019 by Brnich et al.⁷ In addition to measuring truth-set concordance, this methodology stipulates the requirement of an understanding of the disease mechanism, determining if the assay is appropriate for the disease mechanism, and evaluation of the assay experimental method (such as the number of biological and technical replicates).⁷

We previously conducted a workshop in July 2023 at the Wellcome Trust Sanger Institute in Cambridge, UK, bringing together invited international stakeholders from the ClinGen community (attending the 2023 Curating the Clinical Genome meeting) and from the Atlas of Variant Effects (AVE) Alliance community (attending the Mutational Scanning Symposium).⁸ In this half-day workshop, we sought to explore barriers and facilitators to the clinical adoption of MAVEs. Two predominant issues emerged: (1) standards for Brnich-style validation of MAVEs and organizational approaches by which these validations might be undertaken in a timely, accurate, consistent, and efficient fashion and (2) standards for the release of and platforms for clinical display of MAVE data.

A number of international bodies were recognized as potentially relevant to setting standards and/or delivery of Brnich-style validation of MAVEs. As previously stated, the ClinGen SVI Functional WG notably established the initial Brnich et al. methodology (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation). The AVE Alliance was established in 2020 by the community working in MAVEs and has a clinical variant interpretation (CVI) workstream, again established broadly for the same goal.⁹ Variant curation expert panels (VCEPs) have been established by ClinGen: these voluntary, expert-led groups have developed (typically over 1–4 years) individual, gene-level specifications of the 2015 (v.3) ACMG/AMP variant classification framework.¹⁰

The major options for the deposition of MAVE data (beyond individual publications and archived pre-prints) were recognized to be (1) ClinVar and (2) MaveDB.^11,12 There have been comparatively low rates of deposition of variant-level assay and/or MAVE data into ClinVar to date, but as a platform, ClinVar has the advantage of being very familiar to the clinical diagnostic community. MaveDB was established by the AVE Alliance as a repository of MAVE data targeted primarily toward the MAVE-generating scientific community (and is not currently searchable on a per-variant basis).

In the UK, following the adoption of the 2015 (v.3) ACMG/AMP variant classification framework and at the request of the British Association of Genomic Medicine (BSGM) and Association of Clinical Genomic Science (ACGS), the Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017, with monthly meetings held since that date.¹³ Membership comprises 411 National Health Service (NHS) clinical scientists, consultants, clinical geneticists, and genetic counselors from the UK and Republic of Ireland working in the field of cancer susceptibility genetics. An oversight group, the CanVIG-UK Steering Advisory Group (CStAG), also meets monthly, comprising 13 lead clinicians and clinical scientists, providing representation across each regional laboratory group (Genomic Laboratory Hub [GLH]) alongside the central CanVIG-UK team (2–3 clinical research trainees, variously supported by research funding). The goal of CanVIG-UK and CStAG is to generate resources to support consistency in the UK for ACMG/AMP-based variant classification for cancer susceptibility genes, with activities including educational meetings, consultative forums for problematic variants, development of resources such as templates for clinical diagnostic reporting, and development, specification, and ratification of guidance for variant interpretation. One resource developed by CanVIG-UK is a centralized database capturing Brnich-style assay validations performed by the CanVIG-UK central team and collectively via the CanVIG-UK clinical scientist community (https://www.cangene-canvaruk.org/functional-studies-recommendations). Another resource developed and maintained by the CanVIG-UK central team is CanVar-UK, an online platform established in 2017 that hosts variant-level dialogue classifications from the CanVIG-UK clinical scientist community as well as multiple annotations for >1,100,000 variants in 116 cancer susceptibility genes, including data from 23 relevant MAVEs and functional assays (https://canvaruk.org/).¹³

Recognizing the challenges relating to clinical validation and data access for MAVEs, alongside the rapid increase in the publication of these assays, we sought to capture perspectives on these issues directly from those performing ACMG/AMP-based variant classification in a “real-world,” financially constrained healthcare setting. We, therefore, undertook a structured survey of NHS clinical scientists and clinical geneticists through CanVIG-UK.

Subjects and methods

Question content, electronic format, and usability was iterated through several expert groups knowledgeable in ACMG/AMP-based variant classification to ensure that the questions were clear for participants with a clinical background. These groups included The CanVIG-UK Steering and Advisory Group (CStAG; M.D., G.J.B., R.R., A.C., J.F., B.F., S.P.-S., J.G., J.P., T.McD., K.S., H.H., and T.McV.) and members of the AVE Alliance CVI Workstream (AVE-CVI; A.B.S. and R.M.V.) (https://www.varianteffect.org/workstreams) (supplemental methods).

Participants were attendees at the CanVIG-UK monthly meeting on November 15, 2024, who self-selected to participate. Survey data were collected online (http://www.surveymonkey.com), the link to which was circulated to attendees both during the meeting and afterward by email and remained live until November 20, 2024. To provide all participants with an equivalent base level of knowledge regarding MAVE data, the meeting consisted of four talks to introduce the topics surveyed, comprising (1) validation of MAVE data and the Brnich et al. methodology⁷; (2) resources and repositories for accessing MAVE data, including MaveDB, ClinVar, and CanVar-UK; and (3) talks from authors (G.M.F. and D.J.A.) on recently published MAVEs for VHL and BAP1.^14,15

The survey comprised 11 questions relating to the use of MAVE data in NHS clinical diagnostic labs and covered (1) performing clinical validation of MAVE data locally within their own laboratory, (2) processes for clinical validation of MAVE data, centralized versus local, and (3) gene-level and variant-level data required in addition to PS3 and/or BS3 assay-level scores for clinical application of MAVE data (Table S1). The survey received a total of 48 responses of the 86 attendees present at the CanVIG-UK meeting (recruitment rate: 55.8%), all of which were from unique IP addresses. 46/48 responses were from individuals who confirmed regular undertaking of ACMG/AMP-based variant classification for clinically diagnostic reporting, and these 46 results were retained for further analysis.

Figures, counts, and summary statistics were generated using R (v.4.3.0 [2023-04-21 ucrt]¹⁶) and R Studio (v.2024.12.0+467¹⁷).

Results

Participants

Of the 46 participants who confirmed they regularly perform ACMG/AMP-based variant classification for clinical diagnostic reporting, the majority (43/46) were clinical scientists, and the remainder (3/46) were clinical genetics consultants.

Performing clinical validation of MAVE data locally within own laboratory

When asked if they had ever undertaken a Brnich-style validation of any functional assay, just under half of the participants (20/46, 43.5%) responded “yes” (Figure 1A). Participants were then asked, should a new MAVE be published that they would deem to be useful for variant classifications for a gene that they report in their local GLH, whether they would attempt a Brnich-style validation of the MAVE. Only 9 (19.6%) reported that they would attempt the Brnich-style validation of a MAVE themselves. Of the other 37 respondents, 2 (4.3%) stated that they would anticipate that another scientist in their GLH would undertake the validation, 28 (60.9%) would await validation by a central body such as CanVIG-UK or the VCEP, and 7 (15.2%) were unsure of their local processes for validation of functional assays (Figure 1B).

Figure 1.

Results from survey questions pertaining to local clinical validation

n = number of participants.

(A) Number of participants reporting on whether they have or have not ever attempted a Brnich-style validation themselves (n = 46).

(B) Number of participants who would or would not undertake Brnich-style validation for a new MAVE of utility for a gene (n = 46).

(C) Reasons that participants would not attempt a Brnich-style validation locally (n = 37). Participants could select one or more of the given options for this question.

Reasons cited by the 37 respondents who would not attempt a Brnich-style validation themselves included the process being too time consuming (24/37), their lack of confidence in the validation methodology (21/37), their lack of confidence in defining the truth sets (17/37), and the lack of available bioinformatic support within their GLH (e.g., for extracting truth-set variants from ClinVar and aligning them with assay results, 21/37). 12/37 responded that they considered Brnich-style validation beyond the remit of their role (Figure 1C).

Processes for clinical validation of MAVE data: Centralized versus local

Next, participants were asked to consider the situation where authors of a new MAVE have included a Brnich-style validation with assay-level PS3 and/or BS3 scores in their publication. Only 16/46 (34.8%) respondents reported they would be happy to use assay-level PS3 and/or BS3 scores as provided by authors, while 30/46 (65.2%) stated they would require an independent review and/or repeating of the Brnich-style MAVE validation by another body (Figure 2A). When asked from which bodies they would accept such a review, all 30/30 confirmed that CanVIG-UK (CStAG) would be acceptable, 25/30 (83.3%) would accept a review by a relevant VCEP, and 10/30 (33.3%) would accept a review performed within their local GLH (Table S1).

Figure 2.

Results from survey questions on centralized clinical validation

n = number of participants.

(A) Opinions on using assay data where validation was performed only by the MAVE assay authors (n = 46).

(B) Opinions on using pre-print assay data validated by a trusted central body (n = 46).

(C) Confidence of participants who would use validated pre-print assay data (n = 33) that have been validated by each of the listed central bodies, scored from 1 to 5 (1 = very unconfident and 5 = very confident). Mean average and median scores are displayed; mean scores are represented by a red point for each group. One participant did not provide a score for the Atlas of Variant Effects Alliance group (n = 32).

Participants were then asked if they would use unpublished MAVE data available on a pre-print archive such as bioRxiv (https://www.biorxiv.org/) provided that a “reputable body” had reviewed and performed the Brnich-style validation (with display of the resultant assay-level PS3 and/or BS3 scores on a corresponding website or portal). 33/46 (71.7%) confirmed their readiness to use the MAVE data for clinical variant classification in this scenario (Figure 2B). Of these 33 participants, the reported confidence (scored 0–5) was highest if the Brnich-style MAVE validation had been performed (1) centrally by the CanVIG-UK team (CStAG) (median = 5, mean = 4.82) or via the collective CanVIG-UK clinical scientist community (median = 4, mean = 4.24), with assay-level PS3 and/or BS3 scores being displayed on the CanVar-UK web platform in either instance, or (2) the relevant VCEP (median = 5, mean = 4.48) or the ClinGen SVI Functional WG (median = 4, mean = 4.30) with assay-level PS3 and/or BS3 scores being displayed on the ClinGen website in either instance (Figure 2C). The confidence in using the data was lower for Brnich-style MAVE validation performed by the AVE Alliance with assay-level PS3 and/or BS3 scores being displayed on MaveDB (median = 3, mean = 3.25). Confidence was also lower for the Brnich-style MAVE validation being performed locally (median = 3, mean = 3.3).

Gene- and variant-level data were required in addition to assay-level PS3 and/or BS3 scores for clinical application of MAVE data

Finally, participants were asked whether, if provided with assay-level PS3 and/or BS3 scores from a Brnich-style MAVE validation performed by a trusted central body, there were any gene-level or variant-level factors that might influence their application of the prescribed assay-level PS3 and/or BS3 scores for a given variant under evaluation. Scores (1 [low] to 5 [high]) were provided for the likelihood of influencing prescribed assay-level PS3 and/or BS3 scores for two types of assay-level information, namely (1) the type of cell line or (2) the type of assay, and for three types of variant-level information, namely the (3) number and (4) consistency of replicate experiments and (5) how close the absolute functional score was to the lower cutoff threshold. Overall, the majority of participants reported a low likelihood that either gene-level or variant-level factors would influence the assay-level PS3 and/or BS3 scores assigned on Brnich-style MAVE validation when performed by a trusted central body (Figure 3).

Figure 3.

Participant scoring of the likelihood that assay-level information (type of cell line or type of assay) and/or variant-level information (number and consistency of replicates, and absolute functional score) will influence the PS3 and/or BS3 evidence strength applied, scored from 1 to 5 (n = 46; 1 = low likelihood and 5 = high likelihood)

Mean average and median scores are displayed; mean scores are represented by a red point for each group.

Discussion

We present survey data for 46 participants who regularly perform ACMG/AMP-based variant classification for clinical diagnostics, comprising NHS clinical diagnostic scientists (43/46 respondents) and clinical geneticists (3/46). The survey was initiated during a live meeting, preceded by a verbal question-by-question presentation of the full survey. To optimize information, attention, and comprehension by participants, we preceded the delivery of the survey with presentations on (1) Brnich-style validation of MAVEs, (2) available online repositories of MAVE data, and (3) descriptions by authors of two recently published MAVEs. Responses from this relatively homogeneous, NHS-based participant group, all regularly undertaking ACMG/AMP-based variant classification, offer useful insights regarding perspectives on and barriers to the clinical application of MAVE data in a resource-constrained, real-world, clinical diagnostic setting.

While almost half of the participants had previously attempted a Brnich-style validation of a functional assay, only about 20% would proceed in attempting such a validation on a newly published MAVE (specified as being of relevance to a gene they report upon). More than half of the participants cited, by way of explanation, a lack of confidence regarding the Brnich-style validation methodology and uncertainty in assembling appropriate variant truth sets. The majority of participants also reported that they lacked the necessary bioinformatics skills or resources for performing the analyses (for example, extracting truth-set variants from ClinVar and lining them up with assay results). Approximately two-thirds of participants cited time pressures as a barrier, and one-third felt that it was beyond their remit. A number of free-text comments reflected interrelated concerns regarding the Brnich-style validation being performed correctly and the impact of such validation on clinical scientist time: “Clinical scientists are stretched too far already,” “It’s not the most intuitive calculation and would be very time-consuming to do,” “We need extra funding for personnel to perform this task,” “We haven’t defined a formal process to undertake this activity, we would do a superficial review using the Brinch flow chart [sic] rather than a specific assessment,” and one unequivocal response of having “no idea where to start.”

Correlating with reluctance for local Brnich-style MAVE validations was a strong enthusiasm for a trusted central body to take on this role (and make the relevant data available and accessible). Some manner of authorization by such a trusted central body would be deemed necessary by two-thirds of participants even for a MAVE for which the authors had themselves provided a Brnich-style validation and assay-level PS3 and/or BS3 scoring in their publication. For the majority (33/46, 72%) of participants, authorization by the trusted central body superseded the requirement for formal peer-reviewed publication (for example, data only submitted to a pre-publication archive).

There was strong endorsement for both the VCEPs and the ClinGen SVI Functional WG as potential trusted central bodies who might provide Brnich-style validation of new MAVEs (under a hypothetical model that MAVE data and assay-level PS3 and/or BS3 scores would then be made available on ClinVar). The lower enthusiasm for AVE Alliance as a trusted central body may, in part, reflect less familiarity with the group but also may reflect perceptions that MaveDB is less user friendly (as currently configured) for a clinical diagnostic user. Evident from responses was strong support for extant national UK structures already operational in this realm, namely the CanVIG-UK group (with its central team and oversight group CStAG), who already host a central online repository of Brnich-style MAVE validations performed by the CanVIG-UK central team and the collective CanVIG-UK clinical scientist community. By extension, participants also support the presentation of data on CanVar-UK, which is also hosted by CanVIG-UK and which provides variant-level MAVE data alongside other resources relevant to ACMG/AMP-based variant classification. These findings, while supportive of a trusted central body performing Brnich-style validation, also reflect the surveyed population as members of and attendees at CanVIG-UK meetings, who are uniquely familiar with such central support and may provide a more favorable indication toward CanVIG-UK.

Under a hypothetical model of assay-level PS3 and/or BS3 scores from Brnich-style validation being made available for all new MAVEs by some manner of trusted central body, it was then important to elicit which additional assay-level or variant-level annotations might be required alongside assay-level PS3 and/or BS3 scores to support the use of the MAVE data for ACMG/AMP-based variant classifications. The majority of participants reported that there was a low likelihood that further review of assay-level information would cause them to alter the assay-level PS3 and/or BS3 scores provided by the trusted central body, as reflected by one of the free-text comments: “If validated by a recognised trusted group we would not amend the weighting the functional scores determined by that group.” However, caution was voiced by some participants around assay-level issues, for example, the need for a guarantee that the assay “includes ALL mechanisms of disease e.g., missense protein function and potential for LOF via abnormal splicing.” There was a modestly higher mean likelihood that variant-level data annotations may influence assay-level PS3 and/or BS3 scoring, in particular where the variant’s assay score lay close to the absolute assay threshold. One participant cautioned that they “would definitely be more cautious for variants at start/end of exons,” while another emphasized that they would “review publicly available experimental parameters especially if the functional scores applicable according to Brinich seems at odds with other lines of evidence on the specific variant.” It would appear overall that while participants would largely rely on the assay-level PS3 and/or BS3 scores provided by the trusted central body, they would value variant-level data on absolute scores and replicates being provided alongside (to enable review for equivocal variants or particular scenarios). This mirrors findings of polls of other stakeholder groups regarding the clinical application of MAVE data, namely concurrent appetite for wanting just the validated assay-level PS3 and/or BS3 score but also wanting access to extensive variant-level data to accompany the score.^18,19

Limitations of the study

Those attending a CanVIG-UK meeting focused on MAVEs may be a subgroup of CanVIG-UK members skewed by interest in and familiarity with MAVEs. Thus, participants who responded to the poll may be more likely to be actively engaged with using functional evidence and the issues surrounding clinical validation of MAVE data. Only approximately half of the meeting attendees submitted a response, with non-responders likely including clinical geneticists and trainees who do not regularly perform ACMG/AMP-based variant classification but also potentially reflecting individuals less interested, willing, or available to participate in the poll. By virtue of their presence at a CanVIG-UK meeting, participants are also likely to have a positive attitude toward CanVIG-UK as an organization and its current and potential roles for MAVE validation.

It is possible that participants less familiar with functional assays may have misunderstood or lacked knowledge regarding some questions (for example, relating to Brnich-style methodology or the various central bodies), although we had sought to mitigate this with the pre-survey introductory talks and verbal presentation of the survey (and restriction to participants who regularly undertake ACMG/AMP-based variant classification).

The survey findings benefit from the relative homogeneity of participants but necessarily reflect the specific context of UK NHS clinical scientists and clinical geneticists working in cancer susceptibility genetics. A number of the responses relate to UK-specific resources provided and activities undertaken by the CanVIG-UK group (with its central team and oversight group CStAG). No groups equivalent to CanVIG-UK exist for other UK disease subspecialities, so responses might differ regarding the validation of MAVEs if performing the survey within the UK rare disease or cardiac genetics communities.

Conclusions and recommendations

Our survey provides compelling evidence that the (lack of) availability of trusted Brnich-style clinical validations represents a significant potential barrier to the clinical application of new MAVE data. The majority of clinical scientists report that they would be unwilling to use clinical validation metrics provided by MAVE authors but also report that they lack the capacity, confidence, and bioinformatics resources for undertaking the validation locally in their laboratories. This survey relates to the current methodology for Brnich-style MAVE validation (generating assay-level PS3 and/or BS3 scores): it is likely that any new methodologies also incorporating variant-specific validation metrics and/or combining multiple MAVEs for a given gene will prove even more challenging for local laboratories and/or non-experts to perform.

From our survey findings, we identified the following recurring themes, which form a set of recommendations from the collective CanVIG-UK clinical scientist community regarding the integration and use of MAVE data within variant classification.

• (1)A trusted central body or bodies should take responsibility for Brnich-style MAVE validation (rather than individualized laboratories) on account of (1) the consistency and robustness of approach and (2) local staffing implications.

The survey reflects broad support for a number of organizations that might take on this role of a trusted central body: VCEPs, the ClinGen SVI Functional WG, or the AVE Alliance.

However, the ClinGen SVI Functional WG and AVE Alliance, while developing and advising on validation methodology, have not, to date, undertaken Brnich-style validations of individual MAVEs. While VCEPs will variously sanction the application of data from specified assays at specified evidence scores, the rationale, validation methodology, and truth sets used by the VCEP are seldom explicitly provided and are likely widely variable, reflecting the current absence of explicit, unambiguous standardized guidelines (including, for example, combining results available from multiple assays, which may conflict). Furthermore, going forward, the timely and responsive Brnich-style validation of newly released MAVEs is likely to remain challenging for VCEPs, which are volunteer led and operate in delivery cycles of per-gene ACMG/AMP framework specifications that must be centrally approved by the ClinGen SVI before release. Furthermore, for many rare disease genes, no VCEP exists. Although the survey also reflected approval and trust for “mid-scale” models in the form of national trusted central bodies, as exemplified by CanVIG-UK, resourced by a small central team, which can then leverage and coordinate input from the collective clinical diagnostic community, this model will also have challenges.

• (2)Clinically facing displays of MAVE data should include the absolute assay score (variant-level) and the assay-level evidence strength resulting from centralized Brnich-style MAVE validation.

Platforms intending to provide clinically facing displays of MAVE data should be readily accessible and offer user-friendly, variant-level look-up. Incorporation onto platforms already used for querying other data elements relating to ACMG/AMP-based variant classification (such as ClinVar or CanVar-UK) is likely to provide the preferred workflow for accessing MAVE data rather than requiring clinical professionals to access an additional, distinct resource.

• (3)Assay-level and variant-level information should be made available for all variants included in the MAVE publications alongside or readily linked to the clinically facing displays of MAVE data.

Although deemed by the majority of respondents unlikely to influence the clinical application of assay-level PS3 and/or BS3 scores as provided by a central, trusted body, it appeared overall that the routine availability of these data to clinical users would be of value to support the contextualization of MAVE results in equivocal or unusual scenarios.

Consortia

Members of the CanVIG-UK Consortium are C. Turnbull, A. Garrett, L. Loong, S. Choi, B. Torr, S. Allen, M. Durkie, A. Callaway, J. Drummond, G.J. Burghel, R. Robinson, I.R. Berry, A.J. Wallace, D.M. Eccles, M. Tischkowitz, S. Ellard, H. Hanson, E. Baple, D.G. Evans, E. Woodward, F. Lalloo, S. Samant, A. Lucassen, A. Znaczko, A. Shaw, A. Ansari, A. Kumar, A. Donaldson, A. Murray, A. Ross, A. Taylor-Beadling, A. Taylor, A. Innes, A. Brady, A. Kulkarni, A.C. Hogg, A. Ramsay Bowden, A. Hadonou, B. Coad, B. McIldowie, B. Speight, B. DeSouza, B. Mullaney, C. McKenna, C. Brewer, C. Olimpio, C. Clabby, C. Crosby, C. Jenkins, C. Armstrong, C. Bowles, C. Brooks, C. Byrne, C. Maurer, D. Baralle, D. Chubb, D. Stobo, D. Moore, D. O'Sullivan, D. Donnelly, D. Randhawa, D. Halliday, E. Atkinson, E. Rauter, E. Johnston, E. Maher, E. Sofianopoulou, E. Petrides, F. McRonald, F. Pelz, I. Frayling, G. Corbett, G. Rea, H. Clouston, H. Powell, H. Williamson, H. Carley, H.J.W. Thomas, I. Tomlinson, J. Cook, J. Tellez, J. Whitworth, J. Williams, J. Murray, J. Campbell, J. Tolmie, J. Field, J. Mason, J. Burn, J. Bruty, J. Callaway, J. Grant, J. Del Rey Jimenez, J. Pagan, J. VanCampen, J. Barwell, K. Monahan, K. Tatton-Brown, K.R. Ong, K. Murphy, K. Andrews, K. Mokretar, K. Cadoo, K. Smith, K. Baker, K. Brown, K. Reay, K. McKay Bounford, K. Bradshaw, K. Russell, K. Stone, K. Snape, L. Crookes, L. Reed, L. Yarram-Smith, L. Cobbold, L. Walker, L. Walker, L. Hawkes, L. Busby, L. Izatt, L. Kiely, L. Hughes, L. Side, L. Sarkies, K.-L. Greenhalgh, M. Shanmugasundaram, M. Duff, M. Bartlett, M. Watson, M. Owens, M. Bradford, M. Huxley, M. Slean, M. Ryten, M. Smith, M. Ahmed, N. Roberts, O. Middleton, P. Tarpey, P. Logan, P. Dean, P. May, P. Brace, R. Tredwell, R. Harrison, R. Hart, R. Martin, R. Nyanhete, R. Wright, R. Martin, R. Davidson, R. Cleaver, S. Talukdar, S. Butler, J. Sampson, S. Ribeiro, S. Dell, S. Mackenzie, S. Hegarty, S. Albaba, S. McKee, S. Palmer-Smith, S. Heggarty, S. MacParland, S. Greville-Heygate, S. Daniels, S. Prapa, S. Abbs, S. Tennant, S. Hardy, S. MacMahon, T. McVeigh, T. Foo, T. Bedenham, T. Cranston, T. McDevitt, V. Clowes, V. Tripathi, V. McConnell, N. Woodwaer, Y. Wallis, Z. Kemp, G. Mullan, L. Pierson, L. Rainey, C. Joyce, A. Timbs, A.-M. Reuther, B. Frugtniet, B. DeSouza, C. Husher, C. Lawn, C. Corbett, D. Nocera-Jijon, D. Reay, E. Cross, F. Ryan, H. Lindsay, J. Oliver, J. Dring, J. Spiers, J. Harper, K. Ciucias, L. Connolly, M. Tsang, R. Brown, S. Shepherd, S. Begum, S. Daniels, T. Tadiso, T. Linton-Willoughby, H. Heppell, K. Sahan, L. Worrillow, Z. Allen, C. Watt, M. Hegarty, R. Mitchell, R. Coles, G. Nickless, E. Cojocaru, I. Doal, F. Sava, C. McCarthy, R. Jeeneea, D. Goudie, M. McConachie, S. Botosneanu, G. Kavanaugh, K. Russell, C. Sherlaw, O. Tsoulaki, C. Forde, E. Petley, A.-B. Jones, K. Oprych, S. Pryde, Z. Hyder, N. Elkhateeb, R. Braham, L. Hanington, C. Huntley, R. Irving, A. Sadan, M. Ramos, C. Elliot, D. Wren, D. Lobo, J. 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Acknowledgments

We would like to thank the CanVIG-UK members who participated in this survey. A full list of all CanVIG-UK consortium members and their affiliations appears in the supplemental information. S.A. and C.F.R. are supported by CG-MAVE, CRUK Program Award (EDDPGM-Nov22/100004). A.G. and H.H. are supported by CRUK Catalyst Award CanGene-CanVar (C61296/A27223).

Author contributions

Conceptualization, C.T., D.J.A., and G.M.F.; funding acquisition, C.T., D.J.A., and G.M.F.; methodology, C.T., A.G., C.F.R., M.D., G.J.B., R.R., A.C., J.F., B.F., S.P.-S., J.G., J.P., T.McD., K.S., H.H., T.McV., R.M.V., and A.B.S.; investigation, C.T., A.G., and S.A.; data curation, S.A.; formal analysis, S.A.; visualization, S.A.; writing – original draft, C.T. and S.A.; writing – review & editing, all authors.

Declaration of interests

The authors declare no competing interests.

Published: June 5, 2025