Variant reclassification and clinical implications.

Genomic technologies have transformed clinical genetic testing, underlining the importance of accurate molecular genetic diagnoses. Variant classification, ranging from benign to pathogenic, is fundamental to these tests. However, variant reclassification, the process of reassigning the pathogenicity of variants over time, poses challenges to diagnostic legitimacy. This review explores the medical and scientific literature available on variant reclassification, focusing on its clinical implications.Variant reclassification is driven by accruing evidence from diverse sources, leading to variant reclassification frequency ranging from 3.6% to 58.8%. Recent studies have shown that significant changes can occur when reviewing variant classifications within 1 year after initial classification, illustrating the importance of early, accurate variant assignation for clinical care.Variants of uncertain significance (VUS) are particularly problematic. They lack clear categorisation but have influenced patient treatment despite recommendations against it. Addressing VUS reclassification is essential to enhance the credibility of genetic testing and the clinical impact. Factors affecting reclassification include standardised guidelines, clinical phenotype-genotype correlations through deep phenotyping and ancestry studies, large-scale databases and bioinformatics tools. As genomic databases grow and knowledge advances, reclassification rates are expected to change, reducing discordance in future classifications.Variant reclassification affects patient diagnosis, precision therapy and family screening. The exact patient impact is yet unknown. Understanding influencing factors and adopting standardised guidelines are vital for precise molecular genetic diagnoses, ensuring optimal patient care and minimising clinical risk.

Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved].

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.