Variant classification changes over time in BRCA1 and BRCA2

Abstract

Purpose: To report BRCA1 and BRCA2 (BRCA1/2) variant reassessments and reclassifications between 2012 and 2017 at the Advanced Molecular Diagnostics Laboratory (AMDL) in Toronto, Canada, which provides BRCA1/2 testing for patients in Ontario, and to compare AMDL variant classifications with submissions in ClinVar. Methods: Variants were assessed using a standardized variant assessment tool based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology's guidelines and tracked in an in-house database. Variants were shared through the Canadian Open Genetics Repository and submitted to ClinVar for comparison against other laboratories. Results: AMDL identified 1209 BRCA1/2 variants between 2012 and 2017. During this period, 32.9% (398/1209) of variants were reassessed and 12.4% (150/1209) were reclassified. The majority of reclassified variants were downgraded (112/150, 74.7%). Of the reclassified variants, 63.3% (95/150) were reclassified to benign, 20.7% (31/150) to likely benign, 10.0% (15/150) to variant of uncertain significance, 2.0% (3/150) to likely pathogenic, and 4.0% (6/150) to pathogenic. Discordant ClinVar submissions were found for 40.4% (488/1209) of variants. Conclusion: BRCA1/2 variants may be reclassified over time. Reclassification presents ethical and practical challenges related to recontacting patients. Data sharing is essential to improve variant interpretation, to help patients receive appropriate care based on their genetic results.

Reclassification of BRCA1 and BRCA2 variants found in ovarian epithelial, fallopian tube, and primary peritoneal cancers

“…The rate at which specific VUS were reclassified as pathogenic or likely pathogenic variants was 5.6% (6/108) and that specific VUS reclassified as benign or likely benign variants was 27.8% (30/108). These rates were comparable to those observed in previous studies ( Table 4 ) [ 21 ].…”

“…Several studies have shown that about 10%–15% of the cases tested for BRCA exhibited a pathogenic variant [ 20 ]. Further, previous studies have reported a range of prevalence for BRCA VUS (3.9%–22.5%) [ 7 8 9 10 11 21 22 ]. However, these results are primarily from breast cancer studies, as there are very few studies that have solely focused on gynecological oncology.…”

Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time

“…One example of this is the reclassification for BRCA1 and BRCA2 variants over time, most often downgrading. 24,25 Traditionally the classification of (pathogenic) variants was based on the ascertainment from the more severe Mendelian disorders. Now, with more data available from population studies, reduced penetrance of variants is becoming clearer as is demonstrated by these kind of variants found in individuals without a Mendelian phenotype.…”

Clinical Genetic Screening in Adult Patients with Kidney Disease

“…Any discrepancy should be reviewed by both the molecular pathologist and clinician, and prior reports should be reviewed. Importantly, recent data suggest that many VUS will eventually be classified as benign (82)(83)(84)(85)(86) and can usually be resolved with subsequent clinical correlations, in discussions between the molecular diagnostician, clinician, and the patient.…”