Myeloid Malignancies and Acute Myeloid Leukemia Mutation Panels by Next Generation Sequencing

For more information on genomic microarray testing in oncology, see the additional technical information document, Cytogenomic Microarray – Oncology

See Related Tests.

For additional test information, including information on individual tests, refer to the Acute Myeloid Leukemia Molecular Genetic Testing Test Fact Sheet.

Myeloid malignancies are clonal disorders of hematopoietic stem and progenitor cells that include myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). Recent studies have identified recurrently mutated genes with diagnostic and/or prognostic impact in myeloid malignancies. The presence of certain mutations may inform clinical management. This multigene panel by massively parallel sequencing (next generation sequencing) is a more cost-effective approach when compared to the cost of multiple single gene tests. This test can be used to complement the morphologic and cytogenetic workup of myeloid malignancies.

Disease Overview

Diagnostic Issues

  • Genetic targets contained in panels are relevant across the spectrum of myeloid malignancies
  • Identification of one or more clonal genetic abnormalities may aid in establishing the diagnosis and subclassification of a myeloid neoplasm
  • Identification of certain variants or patterns of variants may aid in prognostication and clinical management of patients with a diagnosis of myeloid malignancy

Prognostic and Treatment Issues

  • Certain variants or patterns of variants may have diagnostic or prognostic significance
  • Certain variants may inform clinical management

Genetics

Genes Tested: Myeloid Malignancies Mutation Panel by Next Generation Sequencing

ANKRD26, ASXL1, ASXL2, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CEBPA, CSF3R, CUX1, DDX41, DNMT1, DNMT3A, ELANE, ETNK1, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HNRNPK, IDH1, IDH2, IL7R, JAK1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, LUC7L2, MPL, NOTCH1, NPM1, NRAS, NSD1, PHF6, PIGA, PPM1D, PRPF40B, PRPF8, PTPN11, RAD21, RUNX1, SAMD9, SAMD9L, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG2, STAT3, STAT5B, SUZ12, TET2, TP53, U2AF1, U2AF2, UBA1, WT1, ZRSR2

For some genes, one or more exons of the preferred transcript are not covered by sequencing for the indicated gene. See the Genes Tested table below for full list of targeted regions and exclusions.

Genes Tested: Acute Myeloid Leukemia Mutation Panel by Next Generation Sequencing

ANKRD26, ASXL1, CEBPA, DDX41, DNMT3A, ETV6, FLT3, GATA2, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, RUNX1, TP53, WT1

For some genes, one or more exons of the preferred transcript are not covered by sequencing for the indicated gene. See the Genes Tested table below for full list of targeted regions and exclusions.

Test Interpretation

Results

  • Positive: a somatic variant in one of the tested genes was detected
    • Clinical relevance will be described, if known
  • Negative: no variants were detected in the sequenced genes

Limitations

  • Not intended to detect minimal residual disease (MRD)
  • Variants may be present below the limit of detection (LOD) of 5% allele frequency
  • Variants greater than 24 base pairs may be detected at LOD, but the analytical sensitivity may be reduced
  • Variants may not be identified due to technical limitations in the presence of pseudogenes or in repetitive or homologous regions
  • Variants in regions that are not included in the preferred transcript for the targeted genes will not be detected; see Genes Tested table below for full list of targeted regions and exclusions

Analytic Sensitivity

Variant Class Analytic Sensitivity (PPA)a Estimate (%) Analytic Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

96.9

95.1-98.1

Insertions/duplications (1-24bp)

98.1

95.5-99.3

Insertions/duplications (>24bp)

>99

92.9-100.0

Deletions (1-24bp)

96.7

92.8-98.7

Deletions (>24bp)

90

79.5-96.1

MNVs

97

93.0-99.0

FLT3 ITDs

>99

97.1-100.0

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; ITDs, internal tandem duplications; MNVs, multinucleotide variants; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested by Myeloid Malignancies Mutation Panel by Next Generation Sequencing
Note: the subset of genes tested by Acute Myeloid Leukemia Mutation Panel by Next Generation Sequencing is bolded.
Gene Preferred Transcripta Excluded Exonsb

ANKRD26

NM_014915

ASXL1

NM_015338

ASXL2

NM_018263

BCOR

NM_001123385

BCORL1

NM_021946

BRAF

NM_004333

CALR

NM_004343

CBL

NM_005188

CBLB

NM_170662

CEBPA

NM_004364

CSF3R

NM_156039

CUX1

NM_181552

24

DDX41

NM_016222

DNMT1

NM_001130823

5

DNMT3A

NM_175629

ELANE

NM_001972

ETNK1

NM_018638

ETV6

NM_001987

EZH2

NM_004456

FBXW7

NM_033632

FLT3

NM_004119

GATA1

NM_002049

GATA2

NM_032638

GNAS

NM_000516

HNRNPK

NM_002140

IDH1

NM_005896

IDH2

NM_002168

IL7R

NM_002185

JAK1

NM_002227

JAK2

NM_004972

JAK3

NM_000215

KDM6A

NM_001291415

13

KIT

NM_000222

KMT2A

NM_001197104

KRAS

NM_004985

LUC7L2

NM_016019

MPL

NM_005373

NOTCH1

NM_017617

NPM1

NM_002520

1

NRAS

NM_002524

NSD1

NM_022455

PHF6

NM_001015877

PIGA

NM_002641

PPM1D NM_003620

PRPF40B

NM_001031698

PRPF8

NM_006445

PTPN11

NM_002834

RAD21

NM_006265

RUNX1

NM_001754

SAMD9 NM_017654
SAMD9L NM_152703

SETBP1

NM_015559

SF3B1

NM_012433

SH2B3

NM_005475

SMC1A

NM_006306

SMC3

NM_005445

SRSF2

NM_003016

STAG2

NM_001042749

STAT3

NM_139276

STAT5B

NM_012448

6-9

SUZ12

NM_015355

1-9

TET2

NM_001127208

TP53

NM_000546

U2AF1

NM_006758

U2AF2

NM_007279

UBA1 NM_003334
WT1 NM_024426
ZRSR2 NM_005089

aThis is the transcript number used for analyzing and reporting variants. The transcript version number may change periodically and thus is not listed here. The transcript with version number will be included on the patient's report if a variant is detected in the gene.

bNoncoding exons are not analyzed, except for regions containing known clinically relevant variants in the ANKRD26 5’UTR and NOTCH1 3’UTR. In addition, coding exons noted here are not sequenced due to technical limitations of the assay.