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

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.

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.

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.

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.

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.

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