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BRCA Exchange: “Eliminating variants of uncertain significance in BRCA1,
BRCA2 and beyond”Melissa Cline, UC Santa Cruz Genomics Institute
ITCR Virtual Annual MeetingMay 26, 2020
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Motivation
● ClinVar is full of rare “Variants of Uncertain Significance”.
● Most variant interpretation requires case-level data, which contain PHI and are hard to share.
● The data actually needed for variant interpretation are aggregated summaries, which contain no PHI.
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Aim 1: Federated Data Analysis
“Bringing the code to the data”: for analyzing data that cannot leave its home repository● Analyze sensitive, PHI-containing data “in situ”● Generate aggregated statistics that contain no PHI and
can be shared more openly.
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Aim 2: Integrative Variant Estimation with Saturation Genome Editing (SGE) Functional Assays● Robust variant interpretation
involves assessing many lines of evidence together.
● Cutting-edge SGE functional assays report on thousands of variants in one experiment.
● Develop integrative methods tuned for SGEs.
From Findlay et al, Nature 2018.
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Aim 3: Disseminate the information via GA4GH APIs
● Leverage nascent GA4GH APIs to share data with external repositories.
● Share variant data with CIViC, ClinGen, and others.
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Year 1 Highlights
● Aim 1: Collaborating with BioBank Japan and TOPMed on federated variant analysis.
● Aim 3: Contributing to the GA4GH Variant Representation and Annotation standards. Sharing data via the Variant Representation Standard.
● Aim 3: Defining a standard for federated data entry into ClinGen together with CIViC and other projects.
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AcknowledgementsBenedict PatenZack FischmannAmy CoffinJames CasalettoMary GoldmanCharlie MarkelloLetitia Mueller
Gunnar RätschMarc ZimmermanFaisal Alquaddoomi
Rachel Liao
Lea Starita
BRCA Challenge Steering CommitteeBRCA Challenge Evidence Gathering GroupAmanda SpurdleDavid Goldgar