A comprehensive laboratory‐based program for classification of variants of uncertain significance in hereditary cancer genes

Abstract

Genetic testing has the potential to guide the prevention and treatment of disease in a variety of settings, and recent technical advances have greatly increased our ability to acquire large amounts of genetic data. The interpretation of this data remains challenging, as the clinical significance of genetic variation detected in the laboratory is not always clear. Although regulatory agencies and professional societies provide some guidance regarding the classification, reporting, and long-term follow-up of variants, few protocols for the implementation of these guidelines have been described. Because the primary aim of clinical testing is to provide results to inform medical management, a variant classification program that offers timely, accurate, confident and cost-effective interpretation of variants should be an integral component of the laboratory process. Here we describe the components of our laboratory's current variant classification program (VCP), based on 20 years of experience and over one million samples tested, using the BRCA1/2 genes as a model. Our VCP has lowered the percentage of tests in which one or more BRCA1/2 variants of uncertain significance (VUSs) are detected to 2.1% in the absence of a pathogenic mutation, demonstrating how the coordinated application of resources toward classification and reclassification significantly impacts the clinical utility of testing.

A classification system for clinical relevance of somatic variants identified in molecular profiling of cancer

“…Available resources include recommendations from the American College of Medical Genetics and Genomics (ACMG), 1 the International Agency for Research on Cancer, 2 and others. [3][4][5] The focus of these germ-line variant classification systems is to assign pathogenicity to variants to distinguish known or likely pathogenic variants from benign ones. A clear classification system for reporting variants, particularly if used across multiple laboratories, simplifies variant reporting and highlights significant findings in a potentially complex genetic test report for laboratory clients.…”

“…6 We identified additional studies addressing the determination of whether a constitutional sequence variation is likely a benign polymorphism or a functionally deleterious variant. [2][3][4] Classification and interpretation systems for somatic variants detected via molecular profiling of cancer and other diseases have not yet been established. We conducted a comprehensive search for categorization systems for somatic variants in cancer in PubMed and Google Scholar using various combinations of the following search terms: somatic, cancer, variant, sequence variant, classification, category, categorization, reporting, and guidelines.…”

“…We conducted a comprehensive search for categorization systems for somatic variants in cancer in PubMed and Google Scholar using various combinations of the following search terms: somatic, cancer, variant, sequence variant, classification, category, categorization, reporting, and guidelines. A limited number of relevant articles were identified, with most pertaining to germ-line, [1][2][3][4][5] rather than somatic, findings in cancer. We found only one relevant recent publication on somatic variant classification (SVC) describing a system of prioritization and assigning a level of evidence for clinical actions given a somatic variant found in Submitted Purpose: Interpretation systems for clinical laboratory reporting of genetic variants for inherited conditions have been widely published.…”

Current condition of genetic medicine for hereditary breast cancer

“…Although the clinical trial for this drug has not yet been completed in Japan (16), it may become a promising new drug for patients with BRCA1/2-associated cancer once approved. The frequency of variants of uncertain significance (VUS) on the BRCA1/2 gene was 2-6 % in the Caucasian population in the US (17,18) and this frequency is thought to be greater in other countries with varying ethnic backgrounds due to the small number of patients undergoing BRCA1/2 testing. Therefore proper assessment of VUS has become a major issue in clinical genetic testing.…”

Analysis of BRCA gene missense mutations

“…The detection frequency of VUSs ranges from 2% to 21% among laboratories [9,12,13] . VUSs are sometimes referred to as unclassified variants (UVs).…”