A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes

Abstract

Background Clinical interpretation of genetic test results is complicated by variants of uncertain significance (VUS) that have an unknown impact on health but can be clarified through reclassification. There is little empirical evidence regarding VUS reclassification in oncology care settings, including the prevalence and outcomes of reclassification, and racial/ethnic differences. Methods This was a retrospective analysis of persons with and without a personal history of cancer carrying VUS (with or without an accompanying pathogenic or likely pathogenic [P/LP] variant) in breast, ovarian, and colorectal cancer predisposition genes seen at four cancer care settings (in Texas, Florida, Ohio, and New Jersey) between 2013 and 2019. Results In 2715 individuals included in the study, 3261 VUS and 313 P/LP variants were reported; 8.1% of all individuals with VUS experienced reclassifications and rates varied significantly among cancer care settings from 4.81% to 20.19% (overall p < 0.001). Compared to their prevalence in the overall sample, reclassification rates for Black individuals were higher (13.6% vs. 19.0%), whereas the rates for Asian individuals were lower (6.3% vs. 3.5%) and rates for White and Hispanic individuals were proportional. Two‐year prevalence of VUS reclassification remained steady between 2014 and 2019. Overall, 11.3% of all reclassified VUS resulted in clinically actionable findings and 4.6% subsequently changed individuals' clinical managements. Conclusions The findings from this large multisite study suggest that VUS reclassification alters clinical management, has implications for precision cancer prevention, and highlights the need for implementing practices and solutions for efficiently returning reinterpreted genetic test results.

Genomic disparity impacts variant classification of cancer susceptibility genes in Turkish breast cancer patients

“…The reclassifications are feasible due to the accumulation of larger genome databases and additional supporting evidence. Similarly, variant reclassification has been reported in ancestry‐based studies in underrepresented and diverse ethnic backgrounds 39,49–53 . Therefore, large prospective genetic studies are needed to assess the larger reclassification of variants in Turkish and other populations.…”

“…In our cancer cohort, 6.7% (5/75) of VUS were reclassified to likely benign by using Turkish Variome. Although downgrading VUS to LB might not often affect patient management, this reclassification holds clinical importance 39 . There are reports of diverse practices of surgical procedures for patients with VUS in clinically relevant genes 40–42 .…”

“…Although downgrading VUS to LB might not often affect patient management, this reclassification holds clinical importance. 39 There are reports of diverse practices of surgical procedures for patients with VUS in clinically relevant genes. [40][41][42] Patients with reported VUS experience increased anxiety and even unnecessary procedures.…”

“…Similarly, variant reclassification has been reported in ancestry-based studies in underrepresented and diverse ethnic backgrounds. 39,[49][50][51][52][53] Therefore, large prospective genetic studies are needed to assess the larger reclassification of variants in Turkish and other populations. Furthermore, the development of large gnomAD-like databases representing the Turkish population and making such knowledge bases publicly available is a crucial next step in addressing the current limitations.…”

Validation of the ACMG/AMP guidelines-based seven-category variant classification system

“…Over the past years, we have witnessed near continuous revolution in terms of the standards and rules governing how to weigh and combine evidence with a view to improving our classification of variants, as reflected by the abovementioned works that have attempted to adapt or refine the ACMG/AMP guidelines [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Directly or indirectly related to these adaptations or refinements, variant reclassifications (either upgrades or downgrades) have been a frequent occurrence in the literature (e.g., see recent reports [108][109][110][111][112][113][114][115][116][117][118]. It is our hope that our proposed general variant classification framework will stimulate discussion and debate and lead to further improvements in variant classification.…”