Glossary of Terms

Glossary of Terms
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
Efficacy Evidence 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
CLINICAL TRIALS
REQUIREMENT TYPE
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partial This term is obsolete, and refers to situations where the related molecular profile is either required or excluded from a subset of patients in the trial.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.
EFFICACY EVIDENCE
RESPONSE TYPE
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.
EVIDENCE TYPE
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.
STATUS
Term Definition
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.
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
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 - Meta-analysis A study combining results from multiple validated studies on a subject, including accepted statistical analysis.
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.
FDA approved Information indicating that a given therapy is FDA approved in the context of the associated molecular profile and tumor type
FDA approved - Has Companion Diagnostic General gene variant category listed on drug approval label
FDA approved - On Companion Diagnostic Specific gene variant tested for by approved companion diagnostic
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 0 A Phase 0/Pilot clinical trial
Phase I A Phase I clinical trial
Phase Ib/II A Phase I/Ib clinical trial
Phase II A Phase II clinical trial
Phase III A Phase III clinical trial
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.
Preclinical - Biochemical A preclinical study conducted biochemical analysis only, without cell proliferation, survival, or apoptosis data
Preclinical - Cell culture A preclinical study conducted in established cell lines in culture
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 - 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
VARIANT
VARIANT ENTRY

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

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

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
OTHER
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’.
M1? Indicates a change to the start codon within an unknown affect on protein translation
PROTEIN EFFECT

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.
Generic Terms
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