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Massively Parallel Sequencing
Myeloid malignancies are clonal disorders of hematopoietic stem and progenitor cells that include myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), acute myeloid leukemia (AML), and others. Recent studies have identified recurrently mutated genes with diagnostic, prognostic, and therapeutic impact in myeloid malignancies. The presence of certain variants may inform clinical management.
ARUP’s Myeloid Malignancies Mutation and Copy Number Variation Panel by Next Generation Sequencing (3016621) uses massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) to detect molecular changes (single nucleotide variants [SNVs], small insertions and deletions), copy number variants (CNVs) for the targeted genes, and terminal copy number-neutral loss of heterozygosity (CN-LOH). Myeloid Malignancies Mutation Panel by Next Generation Sequencing (2011117) uses massively parallel sequencing to detect molecular changes including SNVs and small insertions and deletions but does not detect CNVs or CN-LOH. Because these panels overlap, they should not be concurrently ordered. If both panels are ordered on the same specimen, 2011117 will be canceled.
These tests are more cost-effective than multiple single gene tests for the detection of somatic variants in myeloid malignancies and can be used to complement the morphologic and cytogenetic workup of myeloid malignancies.
Disease Overview
Diagnostic, Prognostic, and Treatment Issues
- Targets in this panel are relevant across the spectrum of myeloid malignancies.
- Identification of one or more clonal genetic abnormalities, variants, or patterns of variants may aid in establishing the diagnosis and classification, prognosis, and clinical management of myeloid malignancies.
Genetics
Genes Tested
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. Refer to the Genes Tested table below for full list of targeted regions and exclusions.
Test Interpretation
Results
- Variant classifications:
- Tier 1: Molecular mutations, CNVs, and CN-LOH with known clinical significance in hematologic malignancies
- Tier 2: Variants of unknown clinical significance in hematologic malignancies
- Clinical significance in hematologic malignancies will be described, if known.
Reported Variants
| Myeloid Malignancies Mutation and Copy Number Variation Panel by Next Generation Sequencing (3016621) | Myeloid Malignancies Mutation Panel by Next Generation Sequencing (2011117) | |
|---|---|---|
| Reported | Sequence variants in the preferred transcript CNVs (gains or losses) in the targeted genes Likely acquired terminal CN-LOH CNVs ≥5 Mb in any gene Losses in TBL1XR1, CD200, IKZF1, CDKN2A, ASMTL, ERG, ARID2, ATM Gains in MYC Losses between FIP1LI and PDGFRA that result in a potential fusion Any CN-LOH involving TP53, JAK2, and CBL | Sequence variants in the preferred transcript |
| Not reported | Benign or likely benign variants Likely germline or interstitial CN-LOH Due to the complexity of analysis, CNVs may not be reported in instances of stem cell transplants that present with mixed chimerism, increased genomic complexity (>4 CNVs), and complex aneuploidies (eg, hyper- or hypodiploidy) VAF for CNVs with copy number >3 | Benign or likely benign variants CNVs CN-LOH |
| Mb, megabases; VAF, variant allele fraction | ||
Limitations
- Variants may not be identified due to technical limitations in the presence of pseudogenes or in repetitive or homologous regions.
- Not intended to detect minimal residual disease (MRD).
- Interpretation may be impacted if the patient has had an undisclosed allogeneic bone marrow or stem cell transplant.
- Does not distinguish between somatic and germline variants.
- The Myeloid Malignancies Mutation and Copy Number Variation Panel by Next Generation Sequencing (3016621) does not replace conventional cytogenetic studies or genomic microarray in the workup of hematologic malignancies.
- Neither panel detects the following types of variants:
- Variants in regions that are not included in the preferred transcript for the targeted genes; refer to the Genes Tested table
- RNA variants
- Gene fusions, balanced translocations, and other structural variants
Limit of Detection
- SNVs and variants <24 bp: 5% VAF
- Variants >24 bp may be detected at limit of detection (LOD), but analytic sensitivity may be reduced.
- CNVs (gains and losses): >2 Mb in approximately 30% of the sample
- CN-LOH: >10 Mb in approximately 30% of the sample
- Some areas of the genome may have a reduced sensitivity for CNVs and CN-LOH at LOD.
Analytic Sensitivity
| Variant Class | Analytic Sensitivity (PPA)a Estimate (%) | Analytic Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
| SNVs | 96.9 | 95.1-98.1 |
| Insertions/duplications (1-24 bp) | 98.1 | 95.5-99.3 |
| Insertions/duplications (>24 bp) | >99 | 92.9-100.0 |
| Deletions (1-24 bp) | 96.7 | 92.8-98.7 |
| Deletions (>24 bp) | 90 | 79.5-96.1 |
| MNVs | 97 | 93.0-99.0 |
| FLT3 ITDs | >99 | 97.1-100.0 |
| Copy number gains (>2 Mb) | 91.8 | 86.7-95.3 |
| Copy number losses (>2 Mb) | 92.3 | 87.7-95.5 |
| Copy number-neutral LOH (>10 Mb) | 98.1 | 91.5-99.8 |
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 | ||
Genes Tested
| 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 | — |
| PRPF8 | NM_006445 | — |
| PRPF40B | NM_001031698 | — |
| 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 | — |
| TP53c | 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. cFor detection of sequence variants in the TP53 gene alone, see Somatic TP53 Mutations in Whole Blood and Bone Marrow 3017691. | ||
For more information on ARUP’s AML panels, which include some of the genes in this panel specific to AML, refer to the Acute Myeloid Leukemia Mutation Panel by Next Generation Sequencing and Rapid Acute Myeloid Leukemia Targeted Therapy Mutation Panel Test Fact Sheets.
For detection of sequence variants in the TP53 gene alone, see Somatic TP53 Mutations in Whole Blood and Bone Marrow 3017691.
For more information on ARUP’s genomic microarray test offerings in oncology, refer to the Cytogenomic Microarray - Oncology Test Fact Sheet.