Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR)

Abstract

PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.ca). A total of 5,554 variant observations were submitted; classification differences were identified and comparison reports were sent to participating laboratories. Each site had the opportunity to reclassify variants. The data were analyzed before and after the comparison report process to track concordant- or discordant-variant classifications by three different models.ResultsVariant-discordance rates varied by classification model: 38.9% of variants were discordant when using a five-tier model, 26.7% with a three-tier model, and 5.0% with a two-tier model. After the comparison report process, the proportion of discordant variants dropped to 30.7% with the five-tier model, to 14.2% with the three-tier model, and to 0.9% using the two-tier model.ConclusionWe present a Canadian interinstitutional quality improvement program for DNA-variant interpretations. Sharing of variant knowledge by clinical diagnostic laboratories will allow clinicians and patients to make more informed decisions and lead to better patient outcomes.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results

“…Several studies have reported discrepancy rates in variant interpretation between laboratories; such rates have ranged from 39% to 66%. [24][25][26][27][28] Bland et al (2017) 29 demonstrated that clinician experts' classifications of variants differed from those of laboratories 18% of time, and differences were generally clinically significant. They found that clinicians tended to be more conservative in their classifications.…”

Considerations for clinical curation, classification and reporting of low-penetrance and low effect size variants associated with disease risk

“…The utility of such frameworks is well established and is known to lead to harmonization between clinical laboratories. This is most recently evidenced by the enormous impact of the ACMG/AMP variant classification framework for Mendelian variants 7 , which has become widely used since it was first published in 2015 and which has led to an impressive amount of community harmonization aided by the availability of the ClinVar database and community efforts such as the Clinical Genome Resource (ClinGen) 5,33,34 . Additionally, we raise the question as to which additional factors should guide the inclusion of such variants on clinical reports.…”

Real-world health services utilisation and outcomes afterBRCA1andBRCA2testing in Ontario, Canada: the What Comes Next Cohort Study protocol

“…For women who underwent familial testing, variants will be classified as positive (found to carry a known familial risk-increasing variant) and true negative (not found to carry a known familial variant). For women who underwent sequencing or DHPLC/MLPA, variants will be grouped based on an accepted three-tier classification system 22 : (1) positive (a pathogenic or likely pathogenic variant was identified), (2) inconclusive (a VUS was identified) or (3) negative (a likely benign or benign variant was identified). In this context, a negative test result is non-informative as these women may still harbour a risk-increasing mutation in an untested gene.…”