2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-The ClinGen ENIGMA BRCA1/2 Expert Panel: a dynamic framework for evidence-based recommendations to improve classification criteria for variants in BRCA1/2

The ClinGen ENIGMA BRCA1/2 Expert Panel: a dynamic framework for evidence-based recommendations to improve classification criteria for variants in BRCA1/2

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The ClinGen ENIGMA BRCA1/2 Expert Panel is a group of experts that focuses on improving the classification criteria for variants in the BRCA1/2 genes. They have been curating and re-classifying BRCA1/2 variants, aligning with the ACMG/AMP criteria. By calibrating evidence types and using statistical approaches, they have improved the classification of these variants compared to the original ClinVar classification. The panel has also worked on specifying appropriate weights for different evidence codes and improving consistency between biocurators.<br /><br />The classification of variants in BRCA1 and BRCA2 genes remains a significant issue despite extensive study. The ENIGMA Expert Panel has been working as a ClinGen External Expert Panel since 2015 and has submitted numerous variant classifications to the ClinVar database. They have made updates to their classification criteria and processes to align with the ACMG/AMP criteria and the ClinGen Expert Panel process.<br /><br />The panel consists of experts from various institutions and diagnostic laboratories, primarily in the USA. They have held monthly meetings to discuss the conversion of existing classification criteria to ACMG/AMP codes. They have consulted with the ClinGen Sequence Variant Interpretation group to align with existing clinical practice and have performed calibration of evidence types using statistical methods.<br /><br />The panel has tested the specifications on 40 variants, covering different variant types and classifications. Based on feedback from biocurators, they have made updates to the specifications to improve usability. After aligning the evidence types with the ACMG/AMP criteria, they have assigned weights to different codes based on statistical analysis. They have also repurposed the PM5 code to provide additional evidence for protein termination codon (PTC) variants.<br /><br />Overall, the use of the BRCA1/2 VCEP (Variant Classification Expert Panel) specifications has maintained or improved the classification of the tested variants. However, mRNA splicing data remains challenging to interpret. The panel aims to continue their work on improving the classification criteria for BRCA1/2 variants to address the burden of variants of uncertain significance.

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Presenting Author - Michael T. Parsons, BSc; Co-Author - Michael Anderson, PhD; Co-Author - Windy Berkofsky-Fessler, PhD; Co-Author - Sandrine Caputo, PhD; Co-Author - Raymond Chan, PhD; Co-Author - Melissa S. Cline, PhD; Co-Author - Fergus J. Couch, PhD; Co-Author - Miguel de la Hoya, PhD; Co-Author - Bing-Jian Feng, PhD; Co-Author - David Goldgar, PhD; Co-Author - Encarna Gomez-Garcia, MD; Co-Author - Susan Hiraki, MS, CGC; Co-Author - Megan Holdren, MS, CGC; Co-Author - Claude Houdayer, PhD, MD; Co-Author - Paul James, PhD, MD; Co-Author - Rachid Karam, MD, PhD; Co-Author - Huei San Leong, PhD; Co-Author - Alexandra Martins, PhD; Co-Author - Arjen Mensenkamp, PhD; Co-Author - Alvaro NA. Monteiro, PhD; Co-Author - Vaishnavi Nathan, PhD; Co-Author - Robert O'Connor, PhD; Co-Author - Tina Pesaran, MS, CGC; Co-Author - Paolo Radice, PhD; Co-Author - Marcy E. Richardson, BS, PhD; Co-Author - Gunnar Schmidt, PhD; Co-Author - Inge Sokilde Pedersen, PhD; Co-Author - Melissa Southey, PhD; Co-Author - Sean V. Tavtigian, PhD; Co-Author - Bryony Thompson, PhD; Co-Author - Amanda E. Toland, PhD; Co-Author - Emma Tudini, BSc; Co-Author - Clare A. Turnbull, MD, PhD; Co-Author - Maaike Vreeswijk, PhD; Co-Author - Logan C. Walker, PhD; Co-Author - Lauren Zec, MS, CGC; Co-Author - Amanda B. Spurdle, PhD;

Meta Tag

Bioinformatics

Cancer Syndromes

Genetic Testing

Co-Author Michael Anderson, PhD

Co-Author Windy Berkofsky-Fessler, PhD

Co-Author Sandrine Caputo, PhD

Co-Author Raymond Chan, PhD

Co-Author Melissa S. Cline, PhD

Co-Author Fergus J. Couch, PhD

Co-Author Miguel de la Hoya, PhD

Co-Author Bing-Jian Feng, PhD

Co-Author David Goldgar, PhD

Co-Author Encarna Gomez-Garcia, MD

Co-Author Susan Hiraki, MS, CGC

Co-Author Megan Holdren, MS, CGC

Co-Author Claude Houdayer, PhD, MD

Co-Author Paul James, PhD, MD

Co-Author Rachid Karam, MD, PhD

Co-Author Huei San Leong, PhD

Co-Author Alexandra Martins, PhD

Co-Author Arjen Mensenkamp, PhD

Co-Author Alvaro NA. Monteiro, PhD

Co-Author Vaishnavi Nathan, PhD

Co-Author Robert O'Connor, PhD

Co-Author Tina Pesaran, MS, CGC

Co-Author Paolo Radice, PhD

Co-Author Marcy E. Richardson, BS, PhD

Co-Author Gunnar Schmidt, PhD

Co-Author Inge Sokilde Pedersen, PhD

Co-Author Melissa Southey, PhD

Co-Author Sean V. Tavtigian, PhD

Co-Author Bryony Thompson, PhD

Co-Author Amanda E. Toland, PhD

Co-Author Emma Tudini, BSc

Co-Author Clare A. Turnbull, MD, PhD

Co-Author Maaike Vreeswijk, PhD

Co-Author Logan C. Walker, PhD

Co-Author Lauren Zec, MS, CGC

Co-Author Amanda B. Spurdle, PhD

Presenting Author Michael T. Parsons, BSc

Keywords

ClinGen ENIGMA BRCA1/2 Expert Panel

classification criteria

variants

BRCA1/2 genes

ACMG/AMP criteria

ClinVar classification

evidence types

biocurators

diagnostic laboratories

mRNA splicing data