Rapid communication of efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing

Rehm, Heidi L.

doi:10.1101/mcs.a003467

Cited by 2 publications

(3 citation statements)

References 8 publications

(7 reference statements)

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“…ClinVar, for example, enables selection of variants with higher confident P/LP classification based on star status; however, because the goal of the database is not manual curation but rather to be a repository of community assertions, some well‐established pathogenic variants are marked as conflicting. While recent standards of variant interpretation and broader efforts have helped harmonize some of the discordances within ClinVar (Garber et al, 2016; Harrison et al, 2017, 2018; Henrie et al, 2018; Rehm, 2018; Yang et al, 2017), currently the assigned star status and corresponding interpretations must be used with caution. While our approach currently favors specificity, our manual review process and adaptation of our pipeline allow us to improve our sensitivity as is evidenced by the additional 279 screen‐positive findings (8.2% of overall findings) identified by manually including eight well‐established pathogenic variants that are currently discordant in ClinVar.…”

Section: Challenges and Benefits Encounteredmentioning

confidence: 99%

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Kelly

Leader

Wain

et al. 2021

American J of Med Genetics Pt C

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Exome and genome sequencing are increasingly utilized in research studies and clinical care and can provide clinically relevant information beyond the initial intent for sequencing, including medically actionable secondary findings. Despite ongoing debate about sharing this information with patients and participants, a growing number of clinical laboratories and research programs routinely report secondary findings that increase the risk for selected diseases. Recently, there has been a push to maximize the potential benefit of this practice by implementing proactive genomic screening at the population level irrespective of medical history, but the feasibility of deploying population‐scale proactive genomic screening requires scaling key elements of the genomic data evaluation process. Herein, we describe the motivation, development, and implementation of a population‐scale variant‐first screening pipeline combining bioinformatics‐based filtering with a manual review process to screen for clinically relevant findings in research exomes generated through the DiscovEHR collaboration within Geisinger's MyCode® research project. Consistent with other studies, this pipeline yields a screen‐positive detection rate between 2.1 and 2.6% (depending on inclusion of those with prior indication‐based testing) in 130,048 adult MyCode patient‐participants screened for clinically relevant findings in 60 genes. Our variant‐first pipeline affords cost and time savings by filtering out negative cases, thereby avoiding analysis of each exome one‐by‐one, as typically employed in the diagnostic setting. While research is still needed to fully appreciate the benefits of population genomic screening, MyCode provides the first demonstration of a program at scale to help shape how population genomic screening is integrated into routine clinical care.

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Section: Challenges and Benefits Encounteredmentioning

confidence: 99%

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Kelly

Leader

Wain

et al. 2021

American J of Med Genetics Pt C

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“…Variants of uncertain significance are regularly generated from genome-wide testing and can most easily be resolved through being able to access and explore the context in which such variants have been observed elsewhere (see Figure 1) 6 . Numerous examples exist where making a successful genetic diagnosis has only been possible as a result of being able to access variant and phenotype data from other individuals undergoing testing 7– 11 , and many new genetic causes of disease have been uncovered this way 12, 13 . While most of the published cases are clinician-led, there are an increasing number of patient-led examples of variant sharing that have also catalysed the formation of disease-specific patient support groups and created new avenues of research 14, 15 .…”

Section: Advantages Of Sharing Genetic Variant Datamentioning

confidence: 99%

“…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 .…”

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confidence: 99%

Genomic variant sharing: a position statement

Wright¹,

Ware²,

Lucassen³

et al. 2019

Wellcome Open Res

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Sharing de-identified genetic variant data via custom-built online repositories is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, population controls and correlation with clinical context and family history. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of de-identified genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of genetic variants per individual, associated with limited clinical information, should become standard practice in genomic medicine. Information confirming or refuting the role of genetic variants in specific conditions is fundamental scientific knowledge from which everyone has a right to benefit, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for individual clinical interpretation, it may be more appropriate to use a controlled-access model for such data sharing, with the ultimate aim of making as much information available as possible with appropriate governance.

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Rapid communication of efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing

Cited by 2 publications

References 8 publications

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Leveraging population‐based exome screening to impact clinical care: The evolution of variant assessment in the Geisinger MyCode research project

Genomic variant sharing: a position statement

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