ENIGMA  virtual meeting 2021
October, 5th-7th

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Day 1: General Session - Chairs Mandy Spurdle & Maaike Vreeswijk

Welcome, thanks, housekeeping. Revised Terms of Reference for the Steering Committee, and composition of the SC for the next term – Mandy & Maaike  (slides –  presentation)

Network of interactions with ENIGMA – Mandy (slides presentation, from 14.06 minutes onwards)

Update – BRCA1/2 Expert Panel, including updated use of ACMG/AMP criteria – Michael Parsons (slides – presentation)

Update – ClinGen Hereditary Breast Ovarian Pancreatic Cancer Variant Curation Expert Panel, with a focus on ATM – Marcy Richardson, Fergus Couch, Lidia Feliudabaló (slides – presentation)

BRCA Exchange, GA4GH-related activities, VCEP interactions, ENIGMA Data Focus Group – Melissa Cline (slidespresentation)

Day 1: Pathology Working Group - Chairs Melissa Southey & Mads Thomassen

RAD51 assay as biomarker for functional HR: Progress update – Sara Gutierrez-Enriquez & Maaike Vreeswijk (slides – presentation)

Mutational signatures BRCAx – Mads Thomassen (slides – presentation)

Foundation Medicine data analysis and opportunities for collaboration – Garrett Frampton (slidespresentation

Day 2: Analytical Working Group - Chairs David Goldgar & Kyriaki Michailidoua

Results from the Oncoarray BRCA12 case-control LR analysis – Maria Zanti (slidespresentation part 1, presentation part 2)

BRIDGES in silico missense variants analysis – Leila Dorling (slidespresentation)

CARRIERS missense analysis – Fergus Couch (slides)

Simple method to estimate the proportion of pathogenic variants in case-control data –
Paul James (slidespresentation)

Questions for all speakers
An AWG Simulation Study to answer these questions?

Project ideas – Kyriaki and David (slidespresentation)


Day 2: Functional Working Group - Chairs Maaike Vreeswijk & Alvaro Monteiro

Integrating results from different BRCA2 assays – Alvaro Monteiro (slidespresentation)

“Using a case-control approach to estimate risk associated with RING domain unclassified missense substitutions, stratified by comprehensive mammalian 2-hybrid assay” – Sean Tavtigian (slidespresentationquestions)

BRCA2 hypomorphs – Fergus Couch (Alignment BRCA2 HDR data with Prime editing and Mano B, few slides on PALB2) (slides)

Saturation Genome Editing of PALB2 Reveals Functionally Abnormal Missense Variants –
Lea Starita (slidespresentation)

Functional characterization of CHEK2 VUS – Zdenek Kleibl (slidespresentation)

Functional analysis identifies damaging CHEK2 missense variants associated with increased cancer risk- Rick Boonen. Please contact H.van_Attikum@lumc.nl for more information.

Accessing multiplex assay data for variant interpretation using MaveDB – Alan Rubin (slidespresentation)

Day 3: Splicing Working Group - Chairs Logan Walker & Sara Gutiérrez-Enríquez

Project 7 extension: Building gene specific catalogues of alternative non-BRCA transcripts and PVS1 decision trees – Miguel de la Hoya, Vanessa Lau (slidespresentation)

Use of long reads to assess splicing in full length transcripts – Mads Thomassen, Kathleen Claes (slides  Mads Thomassen – slides Kathleen Claes – presentation)

Using direct cDNA long read sequencing to identify full BRCA isoforms and splicing defects as well as whole transcriptome disruption in BRCA mutations – Jade Forster (slidespresentation)

RNA-Seq analysis of BRCA1/2 mutation carrier LCLs – Jim Fackenthal (slidespresentation)

BRCA1 IVS18 splicing variants – Joanna Domènech, Orland Diez & Sara Gutiérrez-Enríquez (slidespresentation)

BRCA1 IVS11 study – general overview and update – Michael Parsons (slidespresentation)

Altered regulation of BRCA1 exon 11 splicing is associated with breast cancer risk in carriers of BRCA1 pathogenic variants – Gorka Ruiz de Garibay (slides – presentation)

Splice prediction analysis – Score thresholds, tools, deep intronic variants (ENIGMA EP, ClinGen splicing subgroup, Other groups):
• Determining computational splicing prediction thresholds – George Wiggins (slides)presentation)
• Splice prediction analysis for deep intronic variants – Sara Gutiérrez-Enríquez (slidespresentation)

BRCA1/2 Splicing Assay Interpretation – Amanda Spurdle (slidespresentation)

CAGI Project – Diana Baralle (slidespresentation)

Other projects and where to next? (slides presentation)

Day 3: Clinical Working Group - Chairs Arcangela De Nicola & Encarna Gomez-Garcia

Adverts – ongoing projects/new study proposals (slidespresentation)
• Vocabulary Translation Project (VTP) – Arcangela De Nicolo
• Fanconi Anemia – Amanda Spurdle
• BRCA2 R2784Q reduced penetrance – Encarna Gomez-Garcia
• New proposal: CHEK2 and haematological disorders – Encarna Gomez-Garcia

Analysis of deep intronic variants in BRCA1/2 in patients with HBOC and no exonic pathogenic variant detected including large rearrangements – Angela Solano (slidespresentation)

Outcome of breast cancer patients with germline BRCA mutations and new treatment strategies  – Banu Arun (slidespresentation)

Identification of markers of response/resistance to PARP inhibitors and platinums in patients with BRCA positive breast cancer (new project proposal) – Banu Arun (slide 14 from 12.55 onwardspresentation)

Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity – Cristina Fortuno (slidespresentation)

Discussion and Wrap-up (slidespresentation)

Day 3: Sign-off - Mandy Spurdle & Maaike Vreeswijk