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AACR Project GENIE v19.0 · 21,017 myeloid patients Panel-adjusted Fisher's exact with Benjamini-Hochberg FDR N=1 case study · Not clinical guidance

Mutation Profile

Five driver mutations across six oncogenic axes. N=1 myeloid case. MRD-negative, 28+ months post-HSCT.

Gene Variant VAF Domain Classification Actionability
DNMT3A R882H 39% Methyltransferase Pathogenic No direct inhibitor
IDH2 R140Q 2% Active site Pathogenic Enasidenib (FDA 2017)
SETBP1 G870S 34% SKI homology Pathogenic No direct inhibitor
PTPN11 E76Q 29% N-SH2 Pathogenic SHP2 inhibitors (Phase I/II)
EZH2 V662A 59% SET domain Pathogenic Tazemetostat CONTRAINDICATED (LoF)
Mono 7 del(7) — — Adverse IPSS-M risk factor
Cytogenetics Monosomy 7 ELN 2022 Adverse IPSS-M Very High (2.976) Status MRD-negative, full donor chimerism
0 matches in 31,000+ myeloid patients across 10+ databases. Pairwise-corrected expected frequency: 1 in 5.7 billion (677× O/E correction applied).
In 2013, recurrent SETBP1 mutations were identified in the SKI-homologous degron motif of atypical CML patients 1
[1] R 2013
Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013)
PubMedDOI
, independently confirmed by Makishima et al. 2
[2] H 2013
Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013)
PubMedDOI
 This portal extends the SETBP1 partnership landscape to 20,820 myeloid patients in GENIE v19.0 17
[17] Consortium 2017
AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov (2017)
PubMedDOI
, integrating co-occurrence statistics with protein language model scoring 18
[18] Z 2023
Evolutionary-scale prediction of atomic-level protein structure with a language model. Science (2023)
PubMedDOI
, molecular docking, and formal ACMG evidence aggregation across 15 computational tools.
Patients Screened
31,000+
Deduplicated across 10+ databases · 5 driver mutations
Quintuple Matches Zero
0
Pairwise-corrected: 1 in 5.7 billion (677× O/E correction applied)
IPSS-M Risk
Very High
Score: 2.976 · 5 drivers on 6 oncogenic axes
ELN 2022
Adverse
Median OS: 9.7 months (Lachowiez 2023)
Actual Survival Alive
28+ mo
MRD negative, full donor chimerism
DMS Validated
2/5
PTPN11 E76Q (enrichment 0.329) + DNMT3A R882H, wet-lab PS3_Strong

Progressive Mutation Filtering
Zero matches in 31,000+ myeloid patients. That is the empirical finding across GENIE v19.0, cBioPortal (46 studies), GDC (24 projects), ICGC, ClinVar, and 5 additional databases.

The proper math: Under independence, the expected frequency is ~~2.6×10-13 (1 in 3886.3 billion). But the mutations are not independent. We computed the pairwise-corrected estimate using all 10 gene-pair O/E ratios from Fisher's exact test 31
[31] C 2013
Mutational landscape and significance across 12 major cancer types. Nature (2013)
PubMedDOI
:

7 of 10 pairs are enriched (co-occur more than expected): SETBP1+EZH2 (O/E=4.96), SETBP1+PTPN11 (O/E=3.62), PTPN11+EZH2 (O/E=2.91), DNMT3A+IDH2 (O/E=2.74), DNMT3A+PTPN11 (O/E=1.95), IDH2+EZH2 (O/E=1.60), IDH2+PTPN11 (O/E=1.44), DNMT3A+EZH2 (O/E=1.10), DNMT3A+SETBP1 (O/E=1.06). The product of all 10 O/E ratios is 677×, meaning the combination is 677 times more likely than independence predicts.

Corrected estimate: ~1.7×10-10 (1 in 5.7 billion) 30
[30] S 2016
A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence. Genome Biol (2016)
PubMedDOI
. This is the maximum entropy approximation with pairwise constraints, the standard method in cancer genomics. At gene level, the corrected expected count in 21,017 GENIE patients is ~2.0, yet zero were observed, suggesting higher-order exclusion beyond pairwise interactions. PyClone-VI confirms 16
[16] S 2020
PyClone-VI: scalable inference of clonal population structures using whole genome data. BMC Bioinformatics (2020)
PubMedDOI
 a linear evolution model, and at variant level, the profile remains unique on a planetary scale.
Source: AACR Project GENIE v19.0. Panel-eligible myeloid patients after hypermutation filter (>20 coding mutations excluded). Progressive variant-level intersection.

Clinical Annotation

OncoKB
Level 1
IDH2 R140Q: FDA-approved enasidenib
ACMG Classification
5/5 Pathogenic
14-25 evidence points each
ClinGen Validity
7 Definitive
12 gene-disease assertions
Novel Variant
EZH2 V662A
0 PubMed hits, unreported in literature
DMS Validated
2/5
PTPN11 E76Q + DNMT3A R882H, wet-lab PS3_Strong
Two of five variants now have direct experimental functional validation via deep mutational scanning 29
[29] Z 2025
Deep mutational scanning of the multi-domain phosphatase SHP2 reveals mechanisms of regulation and pathogenicity. Nat Commun (2025)
PubMedDOI
: PTPN11 E76Q (enrichment 0.329, 99th percentile of 12,054 SHP2 variants scored) and DNMT3A R882H (Garcia et al. 2025).

Pathogenicity Profile
Figure 2 | Multi-tool pathogenicity concordance for five patient variants. All scores normalized to 0–1. AlphaMissense, CADD PHRED (/40), ESM-2 |LLR| (/12), REVEL, and site conservation shown per variant.
DNMT3A R882H
PP3_Strong
AM: 0.995 | CADD: 28.5 | LLR: -8.383
IDH2 R140Q
PP3_Strong
AM: 0.987 | CADD: 32.0 | LLR: -1.4782
SETBP1 G870S
PP3_Strong
AM: 0.996 | CADD: 28.7 | LLR: -9.8042
PTPN11 E76Q
PP3_Strong
AM: 0.997 | CADD: 28.6 | LLR: -1.8651
EZH2 V662A
PP3_Strong
AM: 0.998 | CADD: 33.0 | LLR: -2.9657
EZH2 V662A reclassification: Initially classified as VUS. Five independent computational models now confirm pathogenicity: AlphaMissense 19
[19] J 2023
Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science (2023)
PubMedDOI
 0.9984, CADD 33.0, REVEL 0.962, EVE 0.9997 (99.995th percentile), ESM-2 18
[18] Z 2023
Evolutionary-scale prediction of atomic-level protein structure with a language model. Science (2023)
PubMedDOI
20
[20] N 2023
Genome-wide prediction of disease variant effects with a deep protein language model. Nat Genet (2023)
PubMedDOI
 LLR=-2.97. This is not a passenger. It is a fifth driver mutation on a sixth oncogenic axis (PRC2-mediated chromatin remodeling). Chase & Cross (Leukemia, 2020) 10
[10] A 2020
Mutational mechanisms of EZH2 inactivation in myeloid neoplasms. Leukemia (2020)
PubMedDOI
 demonstrated that all SET domain missense mutations cause complete or partial loss of H3K27 methylation. Tazemetostat (EZH2 inhibitor) is CONTRAINDICATED because V662A is loss-of-function, not gain-of-function.
Source: AlphaMissense (DeepMind), CADD PHRED (Kircher 2014), ESM-2 masked marginal log-likelihood ratio (Lin 2023). All five variants classified PP3_Strong per ACMG criteria.

Clonal Architecture

PyClone-VI 16
[16] S 2020
PyClone-VI: scalable inference of clonal population structures using whole genome data. BMC Bioinformatics (2020)
PubMedDOI
 formal clonal reconstruction reveals a linear evolution model (log-likelihood -0.51 vs -14.11 for branching). DNMT3A R882H is the founder (CCF 1.00), followed by EZH2 V662A (CCF 0.92), SETBP1 G870S (CCF 0.87), PTPN11 E76Q (CCF 0.74), and IDH2 R140Q as a minor subclone (CCF 0.05). The IDH2+SETBP1 co-occurrence within this patient breaks the population-level mutual exclusivity (OR=0.22 in IPSS-M) 13
[13] E 2022
Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid (2022)
PubMedDOI
.
Source: PyClone-VI (Gillis & Roth, 2020). Cancer cell fractions estimated from variant allele frequencies with purity and ploidy correction.

Oncogenic Convergence
Figure 3 | Oncogenic convergence on MYC. Five driver mutations feed into six distinct pathways, all converging on MYC transcription or protein stability.
Five mutations spanning six oncogenic axes: epigenetic reprogramming (DNMT3A), metabolic transformation (IDH2), RAS-MAPK hyperactivation (PTPN11), PP2A tumor suppressor loss (SETBP1), PRC2 chromatin remodeling (EZH2), and chromosomal instability (monosomy 7). All converge on MYC. Each axis independently promotes MYC transcription or protein stability through distinct molecular mechanisms 12
[12] E 2016
Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med (2016)
PubMedDOI
.

Karyotype: Monosomy 7

Loading karyotype...

45,XY,-7[9]/46,XY[1]. Five somatic driver mutations annotated at genomic positions.

References
  1. Piazza R et al. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nat Genet (2013). PubMed
  2. Makishima H et al. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet (2013). PubMed
  3. AACR Project GENIE Consortium. AACR Project GENIE: powering precision medicine through an international consortium. Cancer Discov (2017). DOI
  4. Lin Z et al. Evolutionary-scale prediction of atomic-level protein structure with a language model. Science (2023). DOI
  5. Kandoth C et al. Mutational landscape and significance across 12 major cancer types. Nature (2013). PubMed
  6. Canisius S et al. A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity. Genome Biol (2016). DOI
  7. Gillis S, Roth A. PyClone-VI: scalable inference of clonal population structures. BMC Bioinformatics (2020). DOI
  8. Papaemmanuil E et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med (2016). PubMed
  9. Cheng J et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science (2023). DOI
  10. Brandes N et al. Genome-wide prediction of disease variant effects with a deep protein language model. Nat Genet (2023). DOI
  11. Bernard E et al. Molecular International Prognostic Scoring System for myelodysplastic syndromes. NEJM Evid (2022). DOI
  12. Jiang Q et al. Deep mutational scanning of PTPN11 SHP2 N-SH2 domain. Blood (2025).
  13. Chase A, Cross NCP. Aberrations of EZH2 in cancer. Leukemia (2020). DOI