Chronic Lymphocytic Leukemia Mutation Panel by Next Generation Sequencing

Last Literature Review: December 2019 Last Update:

For more information on the testing strategy for CLL, refer to ARUP Consult's Chronic Lymphocytic Leukemia topic.

Chronic lymphocytic leukemia (CLL) is a hematopoietic disorder characterized by chronic monoclonal B-cell proliferation. Recent studies have identified recurrently mutated genes with diagnostic and/or prognostic impact in CLL and other lymphoid 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 CLL and other lymphoid malignancies.

Disease Overview

Diagnostic Issues

  • Genetic targets contained in the panel are relevant in CLL and other lymphoid malignancies
  • Identification of one or more clonal genetic abnormalities may aid in establishing the diagnosis of a neoplasm, but results must be interpreted within the context of other clinical and hematologic findings
  • Identification of certain variants or patterns of variants may aid in prognostication of patients with CLL

Prognostic and Treatment Issues

  • Certain variants or patterns of variants may have prognostic significance
  • Certain variants may be sensitive to or provide resistance to targeted therapies

Genetics

Genes Tested

ATM, BCL2, BIRC3, BRAF, BTG1, BTK, CARD11, CD79B, CXCR4, DDX3X, FBXW7, IKZF3, KRAS, MAP2K1, MED12, MGA, MYD88, NOTCH1, NRAS, PLCG2, POT1, RNASEH2A, RNASEH2B, RPS15, SAMHD1, SF3B1, TP53, XPO1, ZMYM3

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

  • A negative result does not exclude a diagnosis of CLL
  • Not intended to detect minimal residual disease (MRD)
  • This test does not determine IGHV mutation status
  • 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
  • Interpretation of this test result may be impacted if this patient has had an undisclosed allogenic bone marrow transplant or stem cell transplant
  • Does not detect translocations, gene rearrangements, copy number alterations, or microsatellite instability
  • Does not distinguish between somatic and germline variants

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

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

bp, base pairs; MNVs, multinucleotide variants; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene Preferred Transcripta, b

ATM

NM_000051

BCL2

NM_000633

BIRC3

NM_001165 (exon 5 excluded)

BRAF

NM_004333

BTG1

NM_001731

BTK

NM_000061

CARD11

NM_032415

CD79B

NM_000626

CXCR4

NM_003467

DDX3X

NM_001193416

FBXW7

NM_033632

IKZF3

NM_012481

KRAS

NM_004985

MAP2K1

NM_002755

MED12

NM_005120

MGA

NM_001164273

MYD88

NM_002468

NOTCH1

NM_017617

NRAS

NM_002524

PLCG2

NM_002661

POT1

NM_015450
RNASEH2A NM_006397
RNASEH2B NM_024570

RPS15

NM_001018 (exon 3 excluded)

SAMHD1

NM_015474

SF3B1

NM_012433

TP53

NM_000546

XPO1

NM_003400

ZMYM3

NM_201599

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 NOTCH1 3’UTR. In addition, coding exons noted here as excluded are not sequenced due to technical limitations of the assay.
Related Information
Chronic Lymphocytic Leukemia - CLL