# Actionability

## Diagnostic

The Diagnostic table provides a list of all the diagnostic assertions from all included sources that have content about the biomarker (i.e., My Knowledge Base, OncoKB, CKB, CIViC).

Classification is adjusted based on the disease.

* If the assertion disease matches the case disease, or any ancestor or descendant diseases, the classification is provided as-is.
* Otherwise, the classification is not provided, and the assertion is sorted to the bottom.

Ancestor and descendant diseases are determined using [SNOMEDCT](https://browser.ihtsdotools.org/?perspective=full\&conceptId1=404684003\&edition=MAIN/2024-08-01\&release=\&languages=en), with the following exceptions:

* Descendents of neoplastic disease do not include ancestors beyond neoplastic disease.
* Non-small cell lung cancer has been added as an ancestor of adenocarcinoma of lung.

You can filter assertions by KB source, disease, or summary. Filter changes are saved and applied across variants within a case and can be reset if needed.

If you have existing knowledge to upload to the system, refer to [Upload Assertions](https://help.connected.illumina.com/connected-insights/configure/du-assertion-upload).

## Therapeutic, Prognostic

The Therapeutic, Prognostic table provides a list of all the therapeutic and prognostic assertions from all included sources that have content about the biomarker (i.e., My Knowledge Base, OncoKB, CKB, CIViC).

Classification is adjusted based on the disease.

* If the assertion disease matches the case disease or any ancestor diseases, the classification is provided as-is.
* If the assertion disease does not match the above diseases and the classification is Tier 1A (or equivalent\*), the classification is provided as Tier 2C (or equivalent\*). OncoKB may not provide a classification in this scenario due to [curation practices](https://sop.oncokb.org/).
* Otherwise, the classification is not provided, and the assertion is sorted to the bottom.

Ancestor diseases are determined using [SNOMEDCT](https://browser.ihtsdotools.org/?perspective=full\&conceptId1=404684003\&edition=MAIN/2024-08-01\&release=\&languages=en), with the following exceptions:

* Descendents of neoplastic disease do not include ancestors beyond neoplastic disease.
* Non-small cell lung cancer has been added as an ancestor of adenocarcinoma of lung.

You can filter by KB source, disease, approval (e.g., FDA, NCCN), or summary. Filter changes are saved and applied across variants within a case and can be reset if needed.

If you have existing knowledge to upload to the system, refer to [Upload Assertions](https://help.connected.illumina.com/connected-insights/configure/du-assertion-upload).

## Classification Mapping

\*Classifications are provided using your [Actionability Classifications](https://help.connected.illumina.com/connected-insights/configure/configuration/c-custom-actionability-classification). If you are using AMP/ASCO/CAP, classifications will be mapped as follows:

<table><thead><tr><th width="196">Connected Insights</th><th>OncoKB</th><th>CKB</th><th>CIViC</th></tr></thead><tbody><tr><td>Tier 1A</td><td>Level 1<br>Level R1<br>Level Px1<br>Level Dx1<br>Level 2<br>Level Px2<br>Level Dx2</td><td>Tier 1A</td><td>Level A</td></tr><tr><td>Tier 1B</td><td>Level 3A<br>Level Px3<br>Level Dx3</td><td>Tier 1B</td><td>Level B</td></tr><tr><td>Tier 2C</td><td>Level 3B</td><td>Tier 2C</td><td>Therapeutic Level C</td></tr><tr><td>Tier 2D</td><td>Level 4<br>Level R2</td><td>Tier 2D</td><td>Non-therapeutic Level C<br>Level D<br>Level E</td></tr></tbody></table>

## Actionability Legend

<table data-header-hidden><thead><tr><th width="186">Column</th><th>Description</th></tr></thead><tbody><tr><td><strong>Field Name</strong></td><td><strong>Description</strong></td></tr><tr><td>Directional Arrows</td><td>Opens to view the assertion summary and update date.</td></tr><tr><td>Source</td><td>Knowledge base origin of the assertion.</td></tr><tr><td>Biomarker</td><td>Indicates how the assertion is related to the variant (for example, specific amino acid change or specific exon change).<br><br>Indicates the TMB, MSI, or GIS status for the clinical trial. This column is available for TMB, MSI, and GIS.</td></tr><tr><td>HRD</td><td>Indicates whether an assertion is associated with HRD positive or negative. This column is available for GIS and variants when the selected transcript is for BRCA1/2.</td></tr><tr><td>Classification</td><td>This column displays the classification (e.g., Tier 1A), as indicated by the knowledge base.</td></tr><tr><td>Type</td><td>Therapeutic, Diagnostic, or Prognostic as indicated by the knowledge base.</td></tr><tr><td>Direction</td><td>• For therapeutic; responsive, nonresponsive, etc., as indicated by the knowledge base.<br>• For prognostic; favorable, unfavorable, etc., as indicated by the knowledge base.</td></tr><tr><td>Therapy</td><td>Therapy for the assertion.</td></tr><tr><td>Disease</td><td>Disease for the assertion.</td></tr><tr><td>Approval</td><td>Authorities that have approved the therapy for the biomarker and disease.<br>• CKB provides FDA, EMA, ANVISA, PDMA, and TGA approvals.<br>• OncoKB level 1 assertions are annotated with FDA.</td></tr><tr><td>Previously Reported Icon</td><td>Any cases where the assertion was previously reported.</td></tr><tr><td>Actions</td><td><p>This column contains the following available actions:<br>• Add to report<br>• Archive, if the assertion is in My Knowledge Base<br>• Copy to New Assertion, if the assertion is not in My Knowledge Base<br></p><p>To edit an assertion, add it to the report before editing. For more information, refer to <a href="../../inter-interp-a-variant/inter-manage-assertions#editing-assertions">Manage Assertions</a>.</p></td></tr></tbody></table>

## Available Knowledge Bases

### Memorial Sloan Kettering OncoKB

Connected Insights provides the Memorial Sloan Kettering OncoKB. For more information, refer to the [OncoKB website](https://www.oncokb.org/). See [this page](https://www.oncokb.org/therapeutic-levels) for classification descriptions.

The following from OncoKB is not supported:

* Non-compliant HGVS
* Unspecified positions: Epigenetic Silencing, ARv567es, AR-V7, DNMT3B7, vIII, vII, vV, TGFBR1\*6A, Overexpression, Wildtype, Promoter Hypermethylation, Hypermethylation, Kinase Domain Duplication, Internal Tandem Duplication, Partial Tandem Duplication

### Genomenon Cancer Knowledge Base (CKB)

Connected Insights provides the Genomenon Cancer Knowledge Base (formerly Jackson Laboratory Clinical Knowledge Base). For more information, refer to the [Genomenon CKB website](https://ckbhome.genomenon.com/). See [this page](https://ckbhome.genomenon.com/about/glossaryOfTerms) for assertion descriptions.

The following from CKB is not supported:

* Complex molecular profiles (for example, co-occuring biomarker assertions)
* Emerging and risk factor evidence types
* Class #, over exp, dec exp, hypermethylation, hypomethylation, dup exonX, dup exonX-X, LOH, loss, positive (except for HRD), and wild type variants.

### Clinical Interpretation of Variants in Cancer (CIViC)

Connected Insights also provides the Clinical Interpretation of Variants in Cancer (CIViC) knowledge base. For more information, refer to the [CIViC website](https://civicdb.org/welcome). See [this page](https://civic.readthedocs.io/en/latest/model/evidence/level.html) for evidence descriptions.

The following from CIViC is not supported:

* Assertions
* Functional and oncogenic evidence types
* Splice Site (c.3028G>A), Boolean-like evidence (for example, (V600E or V600K) and Amplification), Underexpression, Overexpression, Expression, Decreased Peri-therapeutic Expression, Cytoplasmic Expression, Loss, Biallelic Inactivation, Alu Insertion, Alternative Transcript, RSID, Homozygosity, Copy-neutral Loss of Heterozygosity, Cytoplasmic Mislocation, Deleterious Mutation, Double Ph, Wildtype, Domain, Exon-specific fusions