The Role of High Throughput Functional Evidence In Reducing-Population Specific Differences In The Quality of Variant Interpretation
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Authors
Fong, Makenzie
Silkey, Taylor
Issue Date
2022-05-01
Type
thesis_open
Language
Keywords
genetic counseling , variant classification , variant of uncertain significance , genetic testing equity , Medical Genetics
Oncology
Alternative Title
Human Genetics Theses
Abstract
Variants of uncertain significance (VUSs) in cancer pre-disposition genes are more frequent in non-White and/or Hispanic populations than non-Hispanic White (NHW), creating more ambiguity in cancer risk/management for these populations. High throughput functional evidence (HTFE) serves as a powerful classification tool for missense variants within the RING/BRCT domains of BRCA1. We sought to determine if HTFE provides preferential benefit in underrepresented racial and ethnic groups. Our cohort consisted of individuals who had BRCA1 testing and self-reported ancestry as Asian, Black, Hispanic, Middle Eastern, or NHW. For individuals with pathogenic, likely pathogenic, or VUS variants in the RING/BRCT domains, we evaluated the frequency at which HTFE was applied and at which HTFE impacted variant classification, and compared this between non-White and/or Hispanic individuals and NHW individuals using Fisher’s exact test. We found that while application of HTFE between non-White and/or Hispanic individuals (n=140; 64.81%) and NHW individuals (n=240; 69.36%) did not differ, non-White and/or Hispanic individuals (n=67; 31.02%) were more likely to have a variant upgraded due to HTFE than NHW (n=63; 18.21%) (OR=2.0; 95% CI: 1.4-3.0; p
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