Nomenclature of variants and likelihood of being disease causing
| Nomenclature . | Definition . | Likelihood of being disease causing9,19-21 ,* . |
|---|---|---|
| Mutation | “Mutation” is used for germline variations that are pathogenic and found less frequently in a population or are nongermline changes in a tumor cell (somatic mutations).5 | Should only be used when there is clear evidence for pathogenicity |
| Variant | An alteration in the most common DNA nucleotide sequence. The term “variant” can be used to describe an alteration that may be benign, pathogenic, or of unknown significance. The term “variant” is increasingly being used in place of the term “mutation.”22 | Variant is further classified in a 5-tier system: benign, likely benign, uncertain significance, likely pathogenic, pathogenic |
| Benign variant | This variant does not cause disease. | <0.1% |
| Likely benign variant | This variant is not expected to cause disease. Additional evidence may confirm this assertion of benign, but there is a small chance that new evidence may demonstrate that this variant does have clinical significance. | Between 0.1% and 10% |
| Variant of uncertain significance | There is insufficient evidence to put this variant into a benign or pathogenic category. Further evidence, such as population, segregation, or functional data, may up- or downgrade this variant. This variant is not clinically actionable. | Between 10% and 90% |
| Likely pathogenic variant | This variant is expected to cause disease. Additional evidence may confirm this assertion of pathogenicity, but there is a small chance that new evidence may demonstrate that this variant does not have clinical significance. | Between 90% and 99% |
| Pathogenic variant | This variant does cause disease. | >99% |
| Nomenclature . | Definition . | Likelihood of being disease causing9,19-21 ,* . |
|---|---|---|
| Mutation | “Mutation” is used for germline variations that are pathogenic and found less frequently in a population or are nongermline changes in a tumor cell (somatic mutations).5 | Should only be used when there is clear evidence for pathogenicity |
| Variant | An alteration in the most common DNA nucleotide sequence. The term “variant” can be used to describe an alteration that may be benign, pathogenic, or of unknown significance. The term “variant” is increasingly being used in place of the term “mutation.”22 | Variant is further classified in a 5-tier system: benign, likely benign, uncertain significance, likely pathogenic, pathogenic |
| Benign variant | This variant does not cause disease. | <0.1% |
| Likely benign variant | This variant is not expected to cause disease. Additional evidence may confirm this assertion of benign, but there is a small chance that new evidence may demonstrate that this variant does have clinical significance. | Between 0.1% and 10% |
| Variant of uncertain significance | There is insufficient evidence to put this variant into a benign or pathogenic category. Further evidence, such as population, segregation, or functional data, may up- or downgrade this variant. This variant is not clinically actionable. | Between 10% and 90% |
| Likely pathogenic variant | This variant is expected to cause disease. Additional evidence may confirm this assertion of pathogenicity, but there is a small chance that new evidence may demonstrate that this variant does not have clinical significance. | Between 90% and 99% |
| Pathogenic variant | This variant does cause disease. | >99% |
Most variants do not have data to support a quantitative assignment of variant certainty to any of the 5 categories given the heterogeneous nature of most diseases.