Germline Variant Spectrum Among African American Men Undergoing Prostate Cancer Germline Testing: Need for Equity in Genetic Testing

PURPOSE Guidelines for prostate cancer (PCA) germline testing (GT) have expanded, with impact on clinical management and hereditary cancer assessment. African American (AA) men have lower engagement in GT, with concern for widening disparities in genetically informed care. We evaluated the germline spectrum in a cohort of men with PCA enriched for AA men who underwent GT to inform tailored genetic evaluation strategies. METHODS Participants included AA and White men with PCA tested with a 14-gene PCA panel: ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D, and TP53. Germline analysis was performed per standard clinical testing and variant classification protocols. Data were compared with Fisher's exact, chi-squared, or two sample t-tests, as appropriate. Multivariable analysis was conducted using Akaike's Information Criterion. The significance level was set a priori at .05. RESULTS The data set included 427 men all tested using the 14-gene PCA panel: AA (n = 237, 56%) and White (n = 190, 44%). Overall, the pathogenic/likely pathogenic (P/LP) variant rate was 8.2%, with AA men having lower rates of P/LP variants then White men (5.91% v 11.05%, respectively; P = .05). Borderline associations with P/LP variant status were observed by race (AA v White; odds ratio = 0.51; P = .07) and age (> 50 v <= 50 years; odds ratio = 0.48; P = .06). The P/LP spectrum was narrower in AA men (BRCA2, PALB2, ATM, and BRCA1) than White men (BRCA2, ATM, HOXB13, CHEK2, TP53, and NBN). A significant difference was noted in rates of variants of uncertain significance (VUSs) between AA men and White men overall (25.32% v 16.32%; P = .02) and for carrying multiple VUSs (5.1% v 0.53%, P = .008). CONCLUSION Germline evaluation in a cohort enriched for AA men highlights the narrower spectrum of germline contribution to PCA with significantly higher rates of multiple VUSs in DNA repair genes. These results underscore the imperative to engage AA men in GT, the need for larger panel testing in AA men, and the necessity to incorporate novel genomic technologies to clarify VUS to discern the germline contribution to PCA. Furthermore, tailored genetic counseling for AA men is important to ensure understanding of VUS and promote equitable genetics care delivery. PCA germline testing in AA men finds a narrow spectrum of PVs and higher VUS rates: need for genetic engagement, tailored GC, and integration of novel genomic technologies.