Assessing Genetic Variants of Uncertain Significance: The Example of Breast Cancer

Abstract

Abstract Mutations in the BRCA1 or 2 genes can lead to an inherited increased risk of breast, ovarian and other cancers. Molecularly, these mutations manifest primarily as frameshift or nonsense mutations, leading to prematurely truncated proteins that would otherwise function as tumour suppressors. Up to 10–20% of all BRCA mutations are reported as variants of uncertain significance (VUS); these manifest as missense mutations (with resultant amino acid substitution), intronic variants with resultant effect on splicing capacity or in‐frame deletions and insertions, which may or may not change the reading frame of a gene. These variant sequences can confound rather than guide the risk assessment process in the genetic counselling of patients and family members, whether afflicted or not with an actual cancer. Several molecular methods are now able to discriminate those as yet unclassified variants between high and low risk for cancer development; databases have been generated accordingly and may allow some further prediction of the probability of deleterious behaviour. This article aims to clarify the clinical relevance of BRCA VUS, to assimilate resources and make suggestions for estimating their clinical impact, and to highlight the need for further studies in this area. Key Concepts: There are limited guidelines for the specific management and surveillance of patients and their family members who harbour genetic variants of uncertain significance. Integrated models to discriminate high‐risk from low‐risk variants have been generated. Application of these models is considered. Further clinical trials for risk management are advocated. Up to 20% of BRCA 1 and 2 mutations can be missense mutations which amount to variants of uncertain significance, the deleterious nature of which are unclear in clinical practice.