Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

Abstract

The promising expectations about personalized medicine have opened the path to routine large-scale sequencing and increased the importance of genetic counseling for hereditary cancers, among which hereditary breast and ovary cancers (HBOC) have a major impact. High-throughput sequencing, or Next-Generation Sequencing (NGS), has improved cancer patient management, ameliorating diagnosis and treatment decisions. In addition to its undeniable clinical utility, NGS is also unveiling a large number of variants that we are still not able to clearly define and classify, the variants of uncertain significance (VUS), which account for about 40% of total variants. At present, VUS use in the clinical context is challenging. Medical reports may omit this kind of data and, even when included, they limit the clinical utility of genetic information. This has prompted the scientific community to seek easily applicable tests to accurately classify VUS and increase the amount of usable information from NGS data. In this review, we will focus on NGS and classification systems for VUS investigation, with particular attention on HBOCrelated genes and in vitro functional tests developed for ameliorating and accelerating variant classification in cancer.

Challenges of Genomic Testing for Hereditary Breast and Ovarian Cancers

“… 40 The variant classification system involves classes of benign, likely benign, likely pathogenic, and pathogenic. 40 , 41 Assignment of a variant to the correct group allows the proper management of genetic information. An additional group, the largest group with the broadest probability of pathogenicity, is variants of uncertain significance (VUS).…”

“…Due to the location of these variants in non-coding regions or less functionally relevant domains of DNA, the impact of VUS on protein function is more difficult to ascertain compared to known pathogenic variants. 41 The American College of Medical Genetics and Genomics (ACMG) states that variants of uncertain significance should not be used for clinical decision-making. 42 This poses a conundrum for genetic counselors and clinicians when a patient receives a VUS result.…”

“… 44 Better defining of VUS result is a current area of investigation, with in vitro functional assays, algorithms, and updated disease databases all contributing to the goal. 41 The question of who is responsible for recontacting patients as additional information is updated and VUS results become known entities still remains unanswered.…”

“…As noted, NGS describes a high throughput massive parallel sequencing method that enables the rapid sequencing of hundreds of DNA or RNA fragments belonging to the human or tumor genome. 41 , 45 This technique allows for the analysis of single-gene or multi-gene panels. The use of NGS panel testing provides an efficient and cost-effective method for completing genomic testing when multi-gene testing is indicated.…”

The Community Oncology and Academic Medical Center Alliance in the Age of Precision Medicine: Cancer Genetics and Genomics Considerations

“…VUS impose a significant clinical burden. More than one third of NGS-based cancer gene panel tests result in identification of a VUS [ 191 ]; whole exome and genome testing generate even greater numbers of VUS [ 192 , 193 , 194 , 195 ]. Moreover, if a patient belongs to a minority group, for whom genome annotations remain less well confirmed, VUS additionally increase [ 196 ].…”