Putative breast cancer risk variants from populations of South Asian ancestry are under-represented in public variant classification databases

Abstract The majority of publicly available genomics data originates from populations of European ancestry. This limits understanding and detection of inherited genetic risk factors for breast cancer in other populations. To assess the extent to which deficits in knowledge of the genetics of breast cancer risk exist for populations of non-European ancestry, we compared data available on putative breast cancer risk variants in the ClinVar database for populations of different ancestry. Protein-coding insertions and deletions (indels) and single-nucleotide polymorphisms (SNPs) private to populations of Non-Finnish European (NFE), African (AFR), Admixed American (AMR), East Asian (EAS) and South Asian (SAS) ancestry from the Genome Aggregation Consortium (gnomAD v4) were identified for nine established breast cancer risk genes. The percentage of private protein-coding variants listed as ‘Unreported’ by gnomAD in ClinVar were compared between populations. The SAS population had the biggest knowledge deficit, as 43.4% of private SAS variants were not reported in ClinVar, compared to 20–30% for other populations. Proportionally fewer SAS variants were reported for all 9 genes, with the difference reaching an adjusted p