Variants of Unknown Significance Interpretation in Clinical Genomics

Date: Day 1, Wednesday 29th January 2025
Timings: 16:10 - 17:50
Location: The Genome Dome

Many identified variants have uncertain effects on pathogenicity, known as ‘variants of unknown significance’ (VUS). These VUS present a significant challenge to clinicians managing patients with unclear genotype–phenotype relationships. While only a minority of VUS are likely to prove to be pathogenic when later reassessed, the uncertainty adds complexity to clinical decision-making. Current efforts to improve variant interpretation will help to reduce the scope of the problem, but the high prevalence of rare and novel variants in the human genome points to VUS is an ongoing challenge. This workshop aims to discuss strategies that can help mitigate the potential harms of VUS.

Learning Objectives

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  1. Recognize how sharing phenotype-linked variant data advances rare disease diagnosis and research, enhancing the identification and understanding of rare genetic conditions.
  2. Familiarize yourself with tools like DECIPHER that offer powerful interfaces and databases for accurate genomic variant interpretation, supporting diagnosis and research efforts.
  3. Learn and apply ACGS guidelines to score and sub-divide variants of uncertain significance, determine reportable variants, follow recommendations for additional testing, and navigate reclassification for precise genetic analysis.

Workshop Format

Supporting the interpretation and Sharing of Phenotype-Linked Variant Data to Advance Diagnosis and Research

- Understand the importance of data sharing to advance rare disease diagnosis and research

- Familiarise yourself with genotypic and phenotypic resources for genomic variant interpretation

- Overview of DECIPHER’s powerful variant interpretation interfaces

Julia Foreman, DECIPHER Project Leader, EMBL-EBI


Interpretation and Reporting of VUS in Diagnostic Practice

- Supporting the interpretation and Sharing of Phenotype-Linked Variant Data to Advance Diagnosis and Research

- How to score and sub-divide variants of uncertain significance using ACGS guidelines Understanding which variants should be reported and which should not Recommendations for additional testing required after classification

- Guidance on reclassification of variants

Miranda Durkie, Deputy Head of Rare Disease Genomics, North East and Yorkshire Genomic Laboratory Hub Interpretation and Reporting of VUS in Diagnostic Practice


Panel Discussion

This session will host a panel discussion on “Enhancing VUS Interpretation and Integration into Healthcare Practices”

- Kimberly Gilmour, Chief of Laboratory Medicine, Great Ormond Street Hospital for Children

- Emma-Jane Cassidy, Principal Clinical Scientist , Wessex Genomics Laboratory

- Nicky Wiffin, Associate Professor, University of Oxford Panel Discussion

Workshop Leaders

Nicky Whiffin

Associate Professor and Group Leader

Big Data Institute and the Wellcome Centre for Human Genetics

Julia Foreman

DECIPHER Project Leader

EMBL-EBI

Emma-Jane Cassidy

Principal Clinical Scientist and Head of Rare Disease Microarray Section, Wessex Genomics Laboratory Service

Central & South GLH

Kimberly Gilmour

Chief of Laboratory Medicine

Great Ormond Street Hospital for Children

Miranda Durkie

Deputy Head of Rare Disease

Sheffield Children's NHS Foundation Trust