Classification & Risk Stratification Prediction is available for cases created using Connected Insights v5.1+.
If the case disease is Acute Myeloid Leukemia or a subtype, Classification & Risk Stratification Prediction is provided on the Overview Tab.
Classification and risk stratification predictions are based on WHO 2022 and ELN 2022 acute myeloid leukemia guidelines, respectively, focusing on Acute myeloid leukemia with defining genetic abnormalities.
Select a box to review how the evaluation was performed. For more information, refer to Decision Trees below.
The report interpretation summary can be generated from the prediction results by clicking Report.
All variants described below must pass secondary analysis filters (VCF Filter = PASS).
Blast count % ≥ 10
Any of the following:
Detection of PML::RARA fusion in the Variants Tab
Detection of t(15;17)(q24;q21) in the User Determined Karyotype
If the above is met, the classification is predicted to be APL with PML::RARA fusion.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Intermediate.
Blast count % ≥ 10
Any of the following:
Detection of RUNX1::RUNX1T1 fusion in the Variants Tab
Detection of t(8;21)(q21.3;q22.1) in the User Determined Karyotype
The guideline specifies an outdated band 8q22 for RUNX1T1. It is now 8q21.3.
If the above is met, the classification is predicted to be AML with RUNX1::RUNX1T1 fusion.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Favorable.
Blast count % ≥ 10
Any of the following:
Detection of CBFB::MYH11 fusion in the Variants Tab
Detection of inv(16)(p13.1q22.1) in the User Determined Karyotype
Detection of t(16;16)(p13.1;q22.1) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with CBFB::MYH11 fusion.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Favorable.
Blast count % ≥ 10
Any of the following:
Detection of DEK::NUP214 fusion in the Variants Tab
Detection of t(6;9)(p22.3;q34.1) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with DEK::NUP214 fusion.
Adverse
Blast count % ≥ 10
Any of the following:
Detection of RBM15::MRTFA fusion in the Variants Tab
Detection of t(1;22)(p13.3;q13.1) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with RBM15::MRTFA fusion.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Intermediate.
Blast count % ≥ 20
Any of the following:
Detection of BCR::ABL1 fusion in the Variants Tab
Detection of t(9;22)(q34.1;q11.2) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with BCR::ABL1 fusion.
Adverse
Blast count % ≥ 10
Detection of KMT2A structural variant in the Variants Tab
If the above is met, the classification is predicted to be AML with KMT2A rearrangement.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then continue below.
Any of the following:
Detection of MLLT3::KMT2A in the Variants Tab
Detection of t(9;11)(p21.3;q23.3) in the User Determined Karyotype
Detection of KMT2A partial tandem duplication in the Variants Tab
If the above is met, the risk stratification is predicted to be Intermediate. If not, then Adverse.
Blast count % ≥ 10
Any of the following:
Detection of MECOM structural variant in the Variants Tab
Detection of inv(3)(q21.3q26.2) in the User Determined Karyotype
Detection of t(3;3)(q21;q26) in the User Determined Karyotype
Detection of t(3;21)(q26.2;q22) in the User Determined Karyotype
Detection of t(3;12)(q26.2;p13) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with MECOM rearragement.
Adverse
Blast count % ≥ 10
Any of the following:
Detection of NUP98 structural variant in the Variants Tab
Detection of t(5;11)(q35.2;p15.4) in the User Determined Karyotype
Detection of t(11;12)(p15.4;p13.3) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with NUP98 rearrangement.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Intermediate.
Blast count % ≥ 10
Detection of NPM1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
If the above is met, the classification is predicted to be AML with NPM1 mutation.
Any of the following:
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
Detection of DEK::NUP214 fusion in the Variants Tab
Detection of t(6;9)(p22.3;q34.1) in the User Determined Karyotype
Detection of KMT2A structural variant without MLLT3 fusion partner in the Variants Tab
Detection of BCR::ABL1 fusion in the Variants Tab
Detection of t(9;22)(q34.1;q11.2) in the User Determined Karyotype
Detection of KAT6A::CREBBP fusion in the Variants Tab
Detection of t(8;16)(p11.2;p13.3) in the User Determined Karyotype
Detection of MECOM structural variant in the Variants Tab
Detection of inv(3)(q21.3q26.2) in the User Determined Karyotype
Detection of t(3;3)(q21;q26) in the User Determined Karyotype
Detection of t(3;21)(q26.2;q22) in the User Determined Karyotype
Detection of t(3;12)(q26.2;p13) in the User Determined Karyotype
Detection of monosomy 5 in the User Determined Karyotype or Variants Tab
Detection of 5q deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of monosomy 7 in the User Determined Karyotype or Variants Tab
Detection of monosomy 17 in the User Determined Karyotype or Variants Tab
Detection of 17p deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of complex karyotype in the User Determined Karyotype or Variants Tab
Detection of monosomal karyotype in the User Determined Karyotype or Variants Tab
If the above is met, the risk stratification is predicted to be Adverse. If not, then continue below.
Detection of FLT3 internal tandem duplication in the Variants Tab
If the above is met, the risk stratification is predicted to be Intermediate. If not, then Favorable.
None of the classifications above should be met.
Blast count % ≥ 20
Any of the following:
Detection of 2 CEBPA variants in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of CEBPA variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Located in the bZIP domain
The guideline requires biallelic mutations, whereas the evaluation simply checks for 2 due to lack of cis/trans information.
If the above is met, the classification is predicted to be AML with CEBPA mutation.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then continue below.
Detection of CEBPA variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
In-frame (not a frameshift variant)
If the above is met, the risk stratification is predicted to be Favorable. If not, then Intermediate.
None of the classifications above should be met.
Blast count % ≥ 20
Any of the following:
Detection of CBFA2T3::GLIS2 fusion in the Variants Tab
Detection of inv(16)(p13q24) in the User Determined Karyotype
Detection of KAT6A::CREBBP fusion in the Variants Tab
Detection of t(8;16)(p11.2;p13.3) in the User Determined Karyotype
Detection of FUS::ERG fusion in the Variants Tab
Detection of t(16;21)(p11;q22) in the User Determined Karyotype
Detection of MNX1::ETV6 fusion in the Variants Tab
Detection of t(7;12)(q36;p13) in the User Determined Karyotype
Detection of NPM1::MLF1 fusion in the Variants Tab
Detection of t(3;5)(q25;q35) in the User Determined Karyotype
If the above is met, the classification is predicted to be AML with other defined genetic alterations.
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
If the above is met, the risk stratification is predicted to be Adverse. If not, then continue below.
Any of the following:
Detection of KAT6A::CREBBP fusion in the Variants Tab
Detection of t(8;16)(p11.2;p13.3) in the User Determined Karyotype
If the above is met, the risk stratification is predicted to be Adverse. If not, then Intermediate.
None of the classifications above should be met.
Blast count % ≥ 20
Any of the following:
Both of the following:
Detection of complex karyotype in the User Determined Karyotype or Variants Tab
Detection of 5q deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of monosomy 7 in the User Determined Karyotype or Variants Tab
Detection of 11q deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of 12p deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of monosomy 13 in the User Determined Karyotype or Variants Tab
Detection of 17p deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of isochromosome 17q in the User Determined Karyotype
Detection of idic(X)(q13) in the User Determined Karyotype
Detection of ASXL1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of BCOR variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of EZH2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of SF3B1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of SRSF2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of STAG2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of U2AF1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of ZRSR2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
If the above is met, the classification is predicted to be AML, myelodysplasia-related.
Any of the following:
Detection of TP53 variant in the Variants Tab with the following characteristics:
Small variant
Somatic origin (origin = somatic or unknown)
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
VAF ≥ 0.10 (10%)
Detection of monosomy 5 in the User Determined Karyotype or Variants Tab
Detection of 5q deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of monosomy 7 in the User Determined Karyotype or Variants Tab
Detection of monosomy 17 in the User Determined Karyotype or Variants Tab
Detection of 17p deletion in the User Determined Karyotype, or Variants Tab with length ≥ 5 Mbp
Detection of complex karyotype in the User Determined Karyotype or Variants Tab
Detection of monosomal karyotype in the User Determined Karyotype or Variants Tab
Detection of ASXL1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of BCOR variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of EZH2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of SF3B1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of SRSF2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of STAG2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of U2AF1 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
Detection of ZRSR2 variant in the Variants Tab with the following characteristics:
Small variant
Oncogenic or likely oncogenic (as indicated by a knowledge base biological classification or oncogenicity prediction)
If the above is met, the risk stratification is predicted to be Adverse. If not, then Intermediate.
According to WHO/ISCN: ≥ 3 abnormalities, where abnormalities are counted as follows:
Only clonal abnormalities are counted; abnormalities present in only 1 metaphase are ignored.
Numerical gains and losses, simple and complex balanced translocations, unbalanced aberrations involving one chromosome, as well as multiplication of a complete chromosome set are counted as one abnormality.
Unbalanced aberrations involving two or more chromosomes, tetrasomy of same chromosome, triplication or quadruplication, as well as isoderivative chromosomes, are counted as 2 abnormalities.
Constitutional abnormalities are not counted.
In case of multiple clones (subclones or independent clones), chromosome abnormalities in each clone/subclone are counted separately and the number of chromosomal abnormalities is defined by the clone with the highest abnormalities.
For composite karyotypes, clonal chromosomal aberrations are counted in metaphases with the highest number of abnormalities.
According to ELN: Presence of two or more distinct monosomies (excluding loss of X or Y), or one single autosomal monosomy in combination with at least one structural chromosome abnormality.
The Overview tab displays a high-level view of the most relevant variants in the case. This tab contains a list of genes and shows variants detected in that case within those genes. The variants in this list are filtered according to the filter that was selected as part of the test definition. The key genes are predefined by Connected Insights based on cancer type.
The Lab QC section provides an overview of the following information contained under the Lab QC tab:
Metric
Value
Status (Pass/Fail)
For more information on configuring metrics that display in the Lab QC section and their thresholds, refer to Pipeline and QC Configuration.
View the % Estimated Tumor Purity and Estimated Tumor Ploidy in the Overview tab. This information displays under Tumor Characteristics.
The following biomarkers provide an overview of the measurable biological markers. The content in these fields comes from secondary analysis files and is displayed here.
Tumor Mutational Burden (TMB) — Displays the TMB in mut/MB and TMB-Low and TMB-High statuses.
Microsatellite Instability (MSI) — Displays the MSI as a percentage and MS-Stable and MSI-High statuses.
Genomic Instability Score (GIS) — Displays the GIS and GIS-Low and GIS-High statuses.
For more information on setting thresholds for the statuses, refer to Disease Configuration.
Select Interpret to open the biomarker details. For more information, refer to Interpret a Biomarker.
Karyotype can be provided in ISCN format and is used for Classification & Risk Stratification Prediction. Validation is provided to help fix manual errors.
For example,
For more information, refer to Classification & Risk Stratification Prediction.
This section provides information on genes specific to the disease, gene coverage, and variants.
Genes Specific to the Disease
For more information on how to set up genes specific to the disease, refer to Disease Configuration.
Gene Coverage
Gene coverage tracks show the following data in a graph:
Transcript exons and introns — Transcript is the preferred transcript (if specified) or the RefSeq transcript. For more information on specifying a preferred transcript for a gene, refer to Preferred Transcripts.
Gene coverage — The Y-axis indicates the gene coverage (for example, 50X).
Hotspots — Hotspots are plotted along the X-axis and are derived from the Cancer Hotspots website.
Variants — Variants in the gene that pass default filters. For more information on how to set up a default filter, refer to Test Definition Setup.
Gene Expression
Gene expression is shown in transcripts per million (TPM) if provided by the secondary analysis pipeline (e.g., DRAGEN RNA).
Variants
Variants for each gene are shown with My Knowledge Base, Other Knowledge Base assertions, and the default filters that show the variant.
My Knowledge Base assertions include the following classifications:
Highest biological classification across all diseases
Highest actionability classification, including: – Therapeutic classifications across case and ancestor diseases – Prognostic classifications across the case and ancestor diseases – Diagnostic classifications across all diseases
Other Knowledge Base assertions include the following classifications and filters:
Highest biological classification across all diseases for OncoKB
Highest actionability classifications for OncoKB, CKB, CIViC, including: – Therapeutic classifications across case and ancestor diseases – Prognostic classifications across the case and ancestor diseases – Diagnostic classifications across all diseases
To interpret variants from the Overview tab, select Interpret. For more information, refer to Interpret a Biomarker.
