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eMERGE CSG Update HGSC-CL

This update includes the reanalysis of variants and issuing of updated reports, as well as the development of a new CNV method that improves sensitivity and resolution. Six reports have been updated with new CNV findings. Examples of changes include previously undetected exon CNV in MSH2 and reclassification of variants in other genes.

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eMERGE CSG Update HGSC-CL

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  1. eMERGE CSG Update HGSC-CL Eric Venner - 6/20/19

  2. Variant reanalysis and issuing updated reports • Supplement Aims 1a and 3c propose to re-issue reports when variant classifications change • New CNV method published • Improves sensitivity and resolution • 6 reports updated with new CNV findings • (all reports issued) • Example: previously undetected 3 exon CNV in MSH2 Coverage ratio Exons in MSH2

  3. Variant reanalysis and issuing updated reports - cont. • Supplement Aims 1a and 3c propose to re-issue reports when variant classifications change • We developed the ReVU (Reanalysis of Variants and Updater) tool to help with ClinVar reanalysis • From Clinvar, we identified 158 variants with a new Pathogenic classification • All VUS per our initial review • 148 remain VUS, 10 passed on for second review (8 remaining) • Second review ongoing • Examples: • COL3A1 p.Gly532Ser. No ClinVar or literature evidence at the time of review. Now Invitae submitted in 2018 and classified it as LP. • BRCA2, p.Gly2609Val. No clinvar or literature evidence at the time of review. Now Ambry (LP), Invitae (VUS) and GeneDx (VUS) all submitted to ClinVar

  4. Progressive Report updating and alerts ReVU (Reanalysis of Variants and Updater) 1: Identifies internal and external updates, 2: Oversees new reports 3: Alerts, tracks version eDAP • VIP • VIP History Auto ReV VIP VIP History 1. External Reclassification Partial Automation Manual ReV 4. VIP Update 2.a. Auto Update 2 3. Variant Reclassified in Neptune 6. Issue Updated Report & Send Alert 2.b. Manual Update NEPTUNE Harmonization

  5. ARBoR: An Identity and Security Solution for Clinical Reporting Scan barcode, verify & check latest Python API Report histories recorded in encrypted ledger IOS and Android apps Paper accepted in JAMIA

  6. VUS Leans Pathogenic Total 79 variants 50% are cardiomyopathy or arrhythmia genes Common finding: PM1: Hotspot PM2: Absent from controls PP3: In-silico supports damaging

  7. Sex discrepancies • Discussed last time: examining SNPtrace data revealed mismatches with sample metadata • Mismatches confirmed by running the Illumina Core Exome Array • 500K SNP sites, 13K gender sites on X Chromosome • Corrective actions: • Requisition updates • LIMS updates • Corrected reports • Cancelled samples

  8. QC Analysis of X and Y variants As part of QC for the full eMERGE dataset, the coordinating center has been looking at X and Y variants and matching to sample metadata Of interest: Female samples with variants on Y, Male samples with heterozygous variants on X Female samples with variants on Y: largely due to CHEK2 segmental duplication Male samples with het. variants on X less clear but: • a full review of SNPtrace data shows very low contamination • Internal methods assign ‘indeterminate’ sex Down from over 2,400, Continuing to look at ~222 samples. More details in genomics workgroup. Genomic coordinate on Y

  9. FHIR Implementation Project lead by Larry and Mullai Year 5 goals: • Complete a specification which maps the eMERGE reports to the FHIR standard, • Create a pilot implementation, • Work with a clinical site for integration Have assembled an expert panel to discuss open questions. Ex: • How are PGx data represented? • Should recommendations be formally represented in FHIR for later use in decision support? Larry Babb / Mullai Murugan

  10. sequencing Centers UpdateCSG: Partners-Broad

  11. Manuscript Update Submitted Oct 2018 Resubmission #2: June 17th 2019 Contacting all authors soon for affiliations and COI

  12. Sex discrepancy analyses update • Investigated concordance between the requisition-provided sex and the genotype-determined sex from eMERGEseq data for 10,500 samples • Broad-specific fingerprinting assay run in parallel 35 discrepant samples still under investigation, excluded from dbGAP submission

  13. eMERGE III Supplement updates Reported Variants reclassification alerts

  14. eMERGE III Reported Variant Reanalysis Reanalysis of all reported variants and potential reclassification Some updates have already been happening (if variant is reanalyzed by a CSG during the course of eMERGE III) May be prompted by another eMERGE or non-eMERGE case seen in a CSG Also prompted by ClinGen-led variant discrepancy resolution efforts for labs that submit their data to ClinVar as well as ClinGen Expert Panels that prioritize evaluation of variants in ClinVar with discordant interpretations or many VUS submissions

  15. Reclassifications of 11/565 Reported Variants Affecting 23 Reports

  16. Alert notifications: variant reclassification and/or report amendments If a variant has been changed but the report hasn’t been amended, there will be a line through the reported category

  17. Alert notifications: variant reclassification and/or report amendments If a variant has been changed but the report hasn’t been amended, there will be a line through the reported category

  18. Once the report has been amended, the current and reported categories should match Issued 3 updated reports for 1 site per their request. As variants are being reclassified, either when see in other non-eMERGE clinical cases (via alerts) or by systematic reanalysis of reported variants, sites will be consulted for their preferences for next steps.

  19. eMERGE III Supplement updates Variant Reanalysis of suspicious VUSs using eMERGE EHR Data(VUSs that favor/lean towards LP)

  20. 1815 Unique Variants 4327 For analysis 118 VUS-FP Variants 21 Common VUS-FP variants 5432 LB/B excluded VUS-Favor Pathogenic Identification Prioritized variants after filtration Classified as VUS and above 228 Cases Less common variants (seen <3 times) excluded 104 cases across 4 sites

  21. 118 Unique VUS-Favor Pathogenic Variants from LMM in eMERGE III Cohort (40 genes, 228 patients)

  22. VUS-FP variants found in at least 3 individuals (LMM sites only)

  23. Provided sites a list of VUS-leaning path variants, prioritized based on number of observations across eMERGE (seen 3 or more times) Discussion of next steps at Clinical Annotation WG breakout session

  24. Developing ACMG/AMP Criteria Framework for Sub-Classification of VUSs • LMM sub-classifies VUS variants as: • VUS-Favor Pathogenic • VUS • VUS-Favor Benign • No guidance is provided by ACMG/AMP regarding criteria codes to subdivide VUSs • We took 279 variants with VUS subdivisions for which ACMG codes had been assigned to analyze ACMG/AMP evidence base for each • Converted codes to scores weighted by criteria strength using Tavtigian et al 2018 VUS-Favor Benign VUS VUS-Favor Pathogenic Classify as VUS-FP Classify as VUS-FB Need further refinement of rules/codes

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