Prevalence and Reclassification of Genetic Variants in South African Populations with Breast Cancer

ABSTRACT Concurrent testing of numerous genes for hereditary breast cancer (BC) is available but can result in management difficulties. We evaluated use of an expanded BC gene panel in women of diverse South African ancestries and assessed use of African genomic data to reclassify variants of uncertain significance (VUS). A total of 331 women of White, Black African, or Mixed Ancestry with BC had a 9‐gene panel test, with an additional 75 genes tested in those without a pathogenic/likely pathogenic (P/LP) variant. The proportion of VUS reclassified using ClinGen gene‐specific allele frequency (AF) thresholds or an AF > 0.001 in nonguidelines genes in African genomic data was determined. The 9‐gene panel identified 58 P/LP variants, but only two of the P/LP variants detected using the 75‐gene panel were in confirmed BC genes, resulting in a total of 60 (18.1%) in all participants. P/LP variant prevalence was similar across ancestry groups, but VUS prevalence was higher in Black African and Mixed Ancestry than in White participants. In total, 611 VUS were detected, representing 324 distinct variants. 10.8% (9/83) of VUS met ClinGen AF thresholds in genomic data while 10.8% (26/240) in nonguideline genes had an AF > 0.001. Overall, 27.0% of VUS occurrences could potentially be reclassified using African genomic data. Thus, expanding the gene panel yielded few clinically actionable variants but many VUS, particularly in participants of Black African and Mixed Ancestry. However, use of African genomic data has the potential to reclassify a significant proportion of VUS.