Variant Subcategories

Subcategory: Chromosomal Rearrangement

Chromosome Abnormalities Fact Sheet

Inversion

A chromosomal defect in which a segment of the chromosome breaks off and reattaches in the reverse direction.3

Deletion

A portion of the chromosome is missing or deleted.15

Duplication

A portion of the chromosome is duplicated, resulting in extra genetic material.15

Numerical

An individual is either missing one of the chromosomes from a pair or has more than two chromosomes instead of a pair.15

Translocation

Translocation is a type of chromosomal abnormality in which a chromosome breaks and a portion of it reattaches to a different chromosome. Chromosomal translocations can be detected by analyzing karyotypes of the affected cells.4


Subcategory: Germline Variant Classification

Deleterious

See pathogenic or likely pathogenic variant.

Pathogenic Variant

Directly contributes to the development of disease. Additional evidence is not expected to alter the classification of this variant. [Note: Not all pathogenic variants are fully penetrant.]5

Likely Pathogenic Variant

Very likely to contribute to the development of disease, but scientific evidence is currently insufficient to prove this conclusively.5

Variant of Uncertain Significance

There is not enough information at this time to support a more definitive classification of this variant.5

Likely Benign Variant

Not expected to have a major effect on disease, but the scientific evidence is currently insufficient to prove this conclusively.5

Benign Variant

Does not cause disease. Additional evidence is not expected to alter classification of this variant.5


Subcategory: Somatic

A somatic cell is any cell of the body except sperm and egg cells. Somatic cells are diploid, meaning that they contain two sets of chromosomes, one inherited from each parent. Variants in somatic cells can affect the individual, but they are not passed on to offspring.4

Driver Variants (Somatic)

Provides a growth advantage of the cell and is involved in oncoogenesis.9

Passenger Variant (Somatic)

Does not provide a growth advantage of the cell and does not contribute to oncogenesis.9

Copy Number Variation (CNV)

A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next. Following the completion of the Human Genome Project, it became apparent that the genome experiences gains and losses of genetic material. The extent to which copy number variation contributes to human disease is not yet known. It has long been recognized that some cancers are associated with elevated copy numbers of particular genes.4
Copy Number Variation Illustration


Subcategory: Somatic Variant Classification (based on actionability)

Tier I

Variants of strong clinical significance.15
Example:
Level A Evidence
FDA-approved therapy.
Included in professional guidelines.
Level B Evidence
Well-powered studies with consensus from experts in the field.15

Tier II

Variants of potential clinical significance.15
Example:
Level C Evidence
FDA-approved therapies for different tumor types or investigational therapies.
Multiple small published studies with some consensus.
Level D Evidence
Preclinical trials or a few case reports without consensus.15

Tier III

Variants of unknown significance.15
Example: Not observed at a significant allele frequency in the general or specific subpopulation databases, or pan-cancer or tumor-specific variant databases. No convincing published evidence of cancer association.15

Tier IV

Variants of known insignificance (i.e., likely benign or benign).15
Example: Observed at significant allele frequency in the general or specific subpopulation databases No existing published evidence of cancer association.15