| Term | Definition |
|---|---|
| HGNC compliant gene names | |
| HGVS compliant gene variant names where applicable | |
| Consists of one or more variants, encompassing any type of molecular data, and is designed to handle complex genomic signatures | |
| Consists of one or more drugs (i.e., combination therapy) | |
| A group of drugs that have the same target specificity | |
| Either a drug class or a specific therapy assigned to a molecular profile based on documented efficacy | |
| A Disease Ontology DO term | |
| Data from FDA labels, guidelines and published studies connecting a molecular profile to a therapy by indication | |
| Clinical trials conducted in US and Canada from clinicaltrials.gov |
| Term | Definition |
|---|---|
| allowed | This molecular profile is not a requirement for the trial, but patients are allowed to have this molecular profile. This applies mainly to molecular profiles that are typically excluded from trials. |
| diagnostic | This molecular profile is required by some/all of the patients in the trial as part of their diagnosis/histological subtype, is not covered by the relevant disease term, and is not a target of the therapy in the trial. |
| excluded | All patients in the trial are excluded from having this molecular profile. This can be related to the therapy or diagnosis. |
| partial | This term is obsolete, and refers to situations where the related molecular profile is either required or excluded from a subset of patients in the trial. |
| partial - excluded | Some patients in the trial are excluded from having this molecular profile. This can be related to the therapy or diagnosis. |
| partial - required | This molecular profile is required by a subset of patients in the trial, and is a target/rationale for the therapy. This would be applicable in situations where a profile is required for patients with a specific indication, or if a patient has to have one of several different profiles. |
| required | The molecular profile is required by all patients in trial, and is a target/rationale for the therapy. |
| Term | Definition |
|---|---|
| conflicting | Evidence from peer-reviewed published literature from one or more studies demonstrating conflicting evidence that a molecular profile is or is not sensitive to a specific monotherapy or combination therapy. |
| decreased response | Evidence from peer-reviewed published literature demonstrating that treatment with a specific monotherapy or combination therapy results in a decreased response in the context of a specific molecular profile, as compared to another therapy or molecular profile. Decreased response can be used to indicate that a molecular profile is associated with a weaker response to a therapy, however, it may not be considered resistant. |
| no benefit | Evidence from peer-reviewed published literature demonstrating that a specific monotherapy or combination therapy does not benefit a particular tumor type, or there is evidence demonstrating a gene variant or category of variant does not respond to a specific monotherapy or combination therapy. No benefit can in cases where a molecular profile is not sensitive to a therapy, however, this is not due to therapeutic resistance. No benefit can also be used in cases where the addition of a second agent to a therapy does not add benefit over single agent therapy. |
| not applicable | Used with evidence types of emerging, diagnostic, prognostic and risk factor. This is also used in cases where evidence from peer-reviewed published literature demonstrates that a monotherapy or combination therapy is associated with response in a tumor type, but has not been connected to a specific molecular profile or category variant (with profile defined as Unknown unknown). |
| not predictive | Evidence from peer-reviewed published literature from one or more studies demonstrating that a molecular profile does not confer sensitivity or resistance to a specific monotherapy or combination therapy. |
| predicted - resistant | Evidence from peer-reviewed published literature demonstrating that a category of variant or pathway is resistant to a specific monotherapy or combination therapy. This is also appropriate if the evidence described suggests potential resistance, in the cases of evidence related to a single patient, or if the data cannot be accessed, as in a conference abstract. |
| predicted - sensitive | Evidence from peer-reviewed published literature demonstrating that an unspecified variant or pathway is sensitive to a monotherapy or combination therapy. This is also used in cases where the evidence is described as preliminary or modest, the variant is weakly connected to a target, if the data are limited and/or are not supported by functional evidence, or if the data cannot be accessed, as in a conference abstract. |
| resistant | Evidence from peer-reviewed published literature demonstrating and specifying that a molecular profile is resistant to a specific monotherapy or combination therapy. Resistant is used when a molecular profile does not respond to a therapy due to a biochemically supported resistance mechanism, and when resistance is explicitly demonstrated. |
| sensitive | Evidence from peer-reviewed published literature demonstrating that a specific molecular profile is sensitive to a monotherapy or combination therapy. |
| unknown | There is evidence for a therapy in the context of a specific molecular profile, however, the relationship between the efficacy of the therapy and molecular profile is not clear. |
| Term | Definition |
|---|---|
| Actionable | Actionable evidence is clinical or preclinical data supporting a connection between a molecular profile and a drug response. The related response type may be related to sensitivity or resistance. |
| Diagnostic | Diagnostic evidence connects a molecular profile to the diagnosis of a disease. |
| Emerging | Emerging provides evidence for potential development of a molecular profile as a future cancer therapy target. |
| Prognostic | Prognostic evidence connects a molecular profile with disease outcome. |
| Risk Factor | Risk factor evidence connects a germline molecular profile to the risk of disease onset. |
| Term | Definition |
|---|---|
| FDA approved - On Companion Diagnostic | Specific gene variant tested for by approved companion diagnostic |
| FDA approved - Has Companion Diagnostic | General gene variant category listed on drug approval label |
| FDA approved | Information indicating that a given therapy is FDA approved in the context of the associated molecular profile and tumor type |
| FDA contraindicated | Information from the FDA indicating that a given therapy is contraindicated in the context of the associated molecular profile and tumor type |
| Guideline | Information contained in professional guidelines |
| Phase III | A Phase III clinical trial |
| Phase II | A Phase II clinical trial |
| Phase Ib/II | A Phase Ib/II clinical trial |
| Phase I | A Phase I clinical trial |
| Phase 0 | A Phase 0/Pilot clinical trial |
| Expanded access | A clinical trial where enrollment includes patients not eligible to receive the therapy through enrollment on another clinical trial. Also called compassionate use. |
| Clinical Study - Meta-analysis | A study combining results from multiple validated studies on a subject, including accepted statistical analysis. |
| Clinical Study - Cohort | A study comparing outcomes between groups that are similar, with a specific variable characteristic. Cohort studies can be prospective or retrospective and are amenable to statistical analysis. |
| Clinical Study | A study done in patients, outside of a clinical trial, that cannot be classified as a case report, case series, cohort study, or meta-analysis |
| Case Reports/Case Series | Reports on a single patient case or a group or series of cases. Case Reports/Case Series do not include control groups for comparison and do not conduct statistical analysis. |
| Preclinical - Pdx | A preclinical study conducted in patient-derived xenograft (PDX) models |
| Preclinical - Pdx & cell culture | A preclinical study conducted in patient-derived xenograft (PDX) models and cultured cells |
| Preclinical - Cell line xenograft | A preclinical study conducted in cell line xenograft models |
| Preclinical - Patient cell culture | A preclinical study conducted in primary patient cells in culture |
| Preclinical - Cell culture | A preclinical study conducted in established cell lines in culture |
| Preclinical - Biochemical | A preclinical study conducted biochemical analysis only, without cell proliferation, survival, or apoptosis data |
| Preclinical | A preclinical study that cannot be classified as cell-culture, cell-line xenograft, patient cell-culture, or patient-derived xenograft (PDX). For example, a study conducted in a genetically engineered mouse model. |
There are a number of “category” variants that correspond to higher level, non-specific variant types. These are used when the data source does not provide more specificity on the variant.
Category variants are variants that can be considered a parent variant to a group of other variants. These are typically used when a type or group of variants is indicated, but the specific variant is not.
| Term | Definition |
|---|---|
| (X)aa#X | Indicates that the variant results in the replacement of the amino acid at the specified position by another amino acid. The can be considered a category containing any variant resulting in an amino acid substitution at the specified position. An example would be ‘BRAF V600X’. |
| act mut | Indicates that the variant results in a gain of protein function. This can be considered a category containing any variant that results in a gain of function. In some cases, such as with small GTPases, this may indicate that the variant results in a loss of intrinsic function, resulting in activation of downstream signaling. In these cases, this can be considered a category that contains loss of function and/or gain of function variants resulting in downstream pathway activation. |
| class # | Indicates a category of variants with a similar mechanism for activation or inactivation of downstream signaling. This can also indicate a variant belonging to that category. |
| exon # indel | Indicates an insertion (ins) or deletion (del) in the specified exon of the gene. This can be considered a category containing any variant resulting from an insertion or deletion in the specified exon. An example would be ‘FLT3 exon 14 ins’. |
| exonX | Indicates a mutation in the specified exon. This can be considered a category containing any variant within the specified exon. |
| fusion | Indicates a fusion of the gene, but the fusion partner is unspecified. This can be considered a category containing any fusion in which the specified gene is a partner. |
| inact mut | Indicates that the variant results in a loss of protein function. This can be considered a category containing any variant that results in a loss of function. |
| mutant | Indicates an unspecified mutation in the gene. This can be considered a category containing any missense, indel, nonsense, or frameshift variant in the gene. |
| rearrange | Indicates an unspecified rearrangement of the gene. This can be considered a category containing rearrangement of the specified gene. |
Non-specific variants are variants that are not attributed to a specific change in the amino acid or genomic sequence, and are not considered categories.
| Term | Definition |
|---|---|
| amp | Indicates an increased number of copies of the gene and is used in association with CNV |
| dec exp | Indicates decreased expression of the mRNA and/or protein |
| del | Indicates a deletion of the gene and is used in association with CNV |
| high | Indicates a high level. For example, MSI high indicates a high level of microsatellite instability. |
| hypermethylation | Indicates increased methylation of the gene. |
| hypomethylation | Indicates decreased methylation of the gene. |
| LOH | Indicates loss of heterozygosity of the gene, as indicated by loss of one parental copy of the gene. |
| loss | Indicates loss of the gene, mRNA, and protein |
| low | Indicates a low level. For example, MSI low indicates a low level of microsatellite instability. |
| negative | Indicates a lack of expression of mRNA or protein |
| over exp | Indicates overexpression of the mRNA and/or protein |
| positive | Indicates the presence of the gene, mRNA, and protein |
| wild-type | Indicates that no mutation has been detected within the gene |
| Term | Definition |
|---|---|
| del exonX | Indicates a deletion of the entirety of the specified exon. This can be considered a category containing any variant that results in the deletion of the specified exon, but not resulting in deletion of other exons. An example would be ‘MET del exon14’. |
| del exonX-X | Indicates a deletion of the specified exons. |
| dup exonX | Indicates a duplication of the entirety of the specified exon. |
| dup exonX-X | Indicates a duplication of the entirety of the specified exons. |
| M1? | Indicates a change to the start codon within an unknown affect on protein translation |
Protein effect corresponds to the effect of the alteration on the intrinsic activity of the protein. It does not necessarily correspond to downstream pathway activation, etc. (i.e., a loss of function variant may result in pathway activation)
See Protein Effect Decision Matrix| Term | Definition |
|---|---|
| gain of function | There are at least 2 pieces of functional evidence from peer-reviewed published literature demonstrating that the gene alteration present results in increased INTRINSIC activity of the protein. |
| gain of function - predicted | There is peer-reviewed published literature demonstrating that similar gene alterations, both in type and location, have been characterized as gain of function. This is also appropriate if there are limited functional data. |
| loss of function | There are at least 2 pieces of functional evidence from peer-reviewed published literature demonstrating that the gene alteration present results in decreased INTRINSIC activity of the protein. |
| loss of function - predicted | There is peer-reviewed published literature demonstrating that similar gene alterations, both in type and location, have been characterized as loss of function. This is also appropriate if a gene alteration has not been characterized, but all known functional domains or a key domain (i.e. protein kinase domain) are lost, or if there are limited functional data. |
| no effect | There is peer-reviewed published literature with functional evidence demonstrating that the gene alteration present results in activity similar to that of wild-type and does not demonstrate tumorigenic attributes. |
| no effect - predicted | There is peer-reviewed published literature with modest functional evidence demonstrating that the gene alteration present results in activity similar to that of wild-type and does not demonstrate tumorigenic attributes. |
| unknown | There is no peer-reviewed published literature demonstrating the gene alteration present affects the intrinsic activity of the protein. This can also be used when there is conflicting evidence about protein function. |
| Name | Definition |
|---|---|
| Adenocarcinoma of Unknown Primary | Adenocarcinoma for which the tissue of origin cannot be determined |
| Advanced Solid Tumor | A malignant solid tumor |
| Cancer of Unknown Primary | Cancer for which the tissue of origin cannot be determined |
| Carcinoma of Unknown Primary | Carcinoma for which the tissue of origin cannot be determined |
| Indication other than cancer | Indication other than cancer |
| Squamous Cell Carcinoma of Unknown Primary | Squamous cell carcinoma for which the tissue of origin cannot be determined |
| Term | Definition |
|---|---|
| N/A | N/A is used when there is no applicable therapy in the evidence annotation |
| Unknown unknown | Unknown unknown is used when there is no molecular profile associated with the evidence annotation |