Variant of uncertain significance

The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely (i.e. without inherently connoting pathogenicity).

For example, many people know that mutations in the BRCA1 gene are involved in the development of breast cancer because of the publicity surrounding Angelina Jolie's preventative treatment.

[2] Few people are aware of the immense number of other genetic variants in and around BRCA1 and other genes that may predispose to hereditary breast and ovarian cancer.

[1][7][8][9][10] As of 2020[update], there continues to be limited involvement from federal agencies to regulate the clinical validity (accuracy) and utility (risks and benefits) of genetic testing.

[11][12][13] Variant interpretation and classification is notably subjective, as laboratories developed their own criteria prior to the ACMG-AMP guidelines.

[13] Due to the lack of consistency in official guidelines, the genomics community is left struggling to efficiently categorize genetic variants.

A pathogenic variant meets stringent criteria such as evidence from well-established functional studies or being identified in multiple unrelated individuals with the disease.

[17] This category is used for variants that are unlikely to be causative of disease, typically supported by population frequency data or functional studies suggesting no deleterious impact.

[4] Thus, only a small fraction of the almost half-million VUS's that are expected to be identified by whole genome sequencing can be categorized into the 5 categories above, leaving the patient nearly as uninformed about their variants as they would have been without this information.

Changes in those regulatory regions can lead to dysfunction of a gene(s) and produce phenotypic effects that can be relevant to health and function.

Remember, this is only a fraction of the information available world-wide about VUS reports related to breast cancer, and as always, your results may vary.