Interpret a Variant

Connected Insights allows users to create variant interpretation records (assertions). Created assertions are stored in a private database, called My Knowledge Base.

Create Assertions:

• Create assertions from scratch, by editing external knowledge base assertions, or by batch-uploading existing assertions.

• Create four types of assertions: biological, actionability, clinical trials, and gene descriptions

Collaboration and Management:

• Store assertions in a private database, My Knowledge Base.

• Collaborate on interpretation with assigned roles.

• Manage assertions (view, filter, edit, approve, archive) within or outside specific cases.

• Refer to Manage Assertions for more details.

Reporting:

• Include variant assertions in reports individually.

• Include variant assertions in reports through automation. Refer to Report Automation for more details.

• Highlight variants as hereditary risk findings. Refer to Report a Variant as Hereditary Risk Finding

Create New Assertion

For clinical trials and gene descriptions, refer to Create Clinical Trials or Create Gene Descriptions for more details.

From scratch:

• Navigate to the Biomarker Details page.

• Click Create New Assertion in the top-right corner or under the list of reported assertions.

• In the Classification tab, add information to the fields described below.

From an external knowledge base:

• Navigate to the Biomarker Details page.

• Find an assertion from an external knowledge base (e.g., CKB).

• Select the specific assertion and choose Copy to new assertion from the menu next to "Report".

• Add and edit information in the fields described below.

By batch upload existing assertions:

• Refer to Assertion Upload for more details.

Classification Fields

Level

The Level field describes the genomic change for the assertion. It indicates whether the assertion is related to a specific variant, a group of variants, genomic region, and other factors.

Level	Description
Nucleotide	Specific assertion for genome build, chromosome, position, reference allele, and alternate allele. Available for small variants with transcript annotation.
Amino Acid	Specific assertion for amino acid. Available for small variants with HGVSP annotation.
Codon	Specific assertion for codon. Available for small variants with HGVSP and missense consequence annotation.
Exon	Specific assertion for exon. Available for small variants and copy number variants with exon annotation.
Gene	Specific assertion for gene. Available for small variants with gene annotation.
Annotation Overlap	Specific assertion for genome build and genomic range. Available for large variants and RNA splice variants.
Partial Fusion	Specific assertion for at least one gene. Available for RNA fusion variants.
Exact Fusion	Specific assertion for gene, fusion gene, and fusion directionality. Available for structural variants and RNA fusion variants with a fusion gene.

Consequences

The Consequences field further indicates the applicability of the assertion.

For example, if you are creating an assertion for an EGFR exon 19 deletion, regardless of the specific nucleotide change, the assertion can be specified as follows:

• Level: Exon

• Consequence: Inframe deletion

The following consequences are available:

• Gain of function variant

• Loss of function variant

• Transcript consequences

When assertions are matched to variants, the consequences field is matched using an OR logic.

• For example, if an assertion has the stop gained, start lost, and frame shift variant consequences, it can be matched to any variant that has at least one of those consequences.

For biological assertions, if the gain of function variant or loss of function variant is specified, this variant is annotated with these consequences in future cases or if you refresh the case assertions.

• If a variant is annotated with these consequences, then the relevant assertions are shown (e.g., evidence for activating mutations).

Status

The Status field indicates the status of TMB, MSI, and GIS that the assertion is applicable to.

The following categories are available:

• TMB-High

• TMB-Low

• MSI-High

• MS-Stable

• GIS-High

• GIS-Low

HRD

The HRD field indicates if the assertion is related to HRD for GIS and BRCA1 and BRCA2 variants.

The following categories are available:

• Undetermined

• Positive

• Negative

Type

The Type field indicates whether the assertion describes the variant's biological classification or actionability.

The following selections are available:

• Biological

• Therapeutic

• Prognostic

• Diagnostic

Direction

The Direction field indicates the overall observation for the evidence the assertion is describing.

The following selections are available for therapeutic assertions:

• Responsive

• Non-Responsive

• Contraindicated

The following selections are available for prognostic assertions:

• Favorable

• Unfavorable

Therapy

The Therapy field indicates the therapy context for the assertion. This field is only available for therapeutic assertions.

• To add a drug, search for drug names using RxNorm terms.

• For assertions with drug combinations, select more than one drug in the same assertion. For assertions with a single drug, select one drug per assertion.

Disease

The Disease field indicates the disease context for the assertion.

• Diseases can be searched using SNOMEDCT terms.

• For Biological assertions, the default selection is neoplastic disease.

• For all other assertions, the default is the disease of the case.

Classification

The Classification field is used to specify the biological or actionability classification.

For biological assertions:

• Available selections are Oncogenic, Likely Oncogenic, Pathogenic, Likely Pathogenic, VUS, Likely Benign, and Benign.

For actionability assertions:

• The default selections are based on Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.

• To set up your own classification categories, following the guidance in Custom Actionability Classification

Summary

The Summary field is a free text field for an assertion summary. The summaries are displayed in the report.

Notes

The Notes field is a free text field for internal notes related to the assertion. The notes are not displayed in the report.

Approval Status

The Approval Status field indicates the assertion approval status. See Manage Assertions for more details.

Report a Variant as Hereditary Risk Finding

Reports can indicate hereditary risk findings to list variants suspected or confirmed to be of germline origin that could be associated with hereditary cancer risk. To indicate a variant is a hereditary risk finding in the report:

• Navigate to the Biomarker Details page.

• Create or report at least one assertion.

• Select the Also report as a hereditary risk finding? checkbox that appears in the top-right corner.