Abstract B076: Germline variation in cancer susceptibility genes among Black cancer survivors in the Reclassifying Variants for Equity in Clinical Care (REVEAL) study

Abstract

Black cancer survivors who undergo clinical genetic testing are more likely to carry variants of uncertain significance (VUS) than White survivors. VUS lack evidence for clinical intervention, leaving patients with confusion and anxiety. We characterized variation in known cancer susceptibility genes in a large cohort of Black cancer survivors with a focus on identifying VUS that could be reclassified using family studies and high throughput functional assays. The goal of the Reclassifying Variants for Equity in Clinical Care (REVEAL) study is to implement an integrative approach for re-classifying VUS and identifying novel pathogenic variants through targeted germline sequencing, familial segregation analyses, and somatic mutation profiling of tumors within the Detroit Research on Cancer Survivors (ROCS) study. We analyzed 46 inherited cancer genes with actionable clinical guidelines using germline whole-genome sequencing data from 1,745 Detroit ROCS participants [Breast (BC) n=655, Prostate (PC) n=727, Colorectal (CRC) n=191, Endometrial (EC) n=82, other young onset (OYO) n=90]. We retained single nucleotide variants and short insertions/deletions not in repetitive regions with minor allele frequency (AF) ≤1% in African ancestry populations (1000 Genomes, ExAC, gnomAD), predicted protein-coding or canonical splice impact, and cohort AF ≤ 1%. ClinVar linkage and Ensembl Variant Effect Predictor v114 were used for functional annotation. Modified American College of Medical Genetics and Genomics (ACMG) guidelines were applied to identify VUS requiring familial segregation and/or functional data for reclassification. A total of 4,885 variants (n=1,749 unique) were retained after filtering. Of the 1,749 unique variants, ClinVar linkage identified 1,066 as VUS while 308 were not reported in the database. VUS were most commonly found in ATM among BC, CRC, PC, and OYO (8.8-19.0% of VUS), while RET VUS were most common in EC (15.0% of VUS). VUS were also commonly identified within the following genes (% of VUS in a given gene within each cancer site): APC (BC 9%, PC 6.5%, OYO 9.5%), BRIP1 (OYO 14.3%), CDKN2A (OYO 9.5%), CHEK2 (OYO 14.3%), EPCAM (OYO 9.5%), MLH1 (CRC 7.5%), MSH6 (OYO 9.5%), NF1 (EC 10%), PTCH1 (CRC 12.5%), and SDHA (BC 5.5%, EC 10%, PC 5.9%). Among 1,374 VUS/unclassified variants, 794 (57.8%) could be reclassified as pathogenic or likely pathogenic with additional evidence from familial segregation or functional studies (53 require either type of evidence, 580 require functional evidence, 161 require both). These potentially reclassifiable VUS were identified in 1,299 participants (464 BC, 142 CRC, 60 EC, PC 571, 62 OYO). These findings show a high burden of VUS among Black cancer survivors and highlight opportunities for systematic VUS reclassification. Shaomiao Xia, Yue Zhao, Anthony Scott, Sarah Austin, Angela Trepanier, Lara Sucheston-Campbell, Alicia Salkowski, Julie Ruterbusch, Angela Wenzlaff, Tingting Qin, Maureen Sartor, Jennifer L. Beebe-Dimmer, Ann G. Schwartz, Elena M. Stoffel, Kristen S. Purrington, Savannah Lane. Germline variation in cancer susceptibility genes among Black cancer survivors in the Reclassifying Variants for Equity in Clinical Care (REVEAL) study [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr B076.