Purpose: To present results from a large cohort of individuals receivingexpanded carrier screening (CS) in the United States.Methods: Single-gene disorder carrier status for 381,014 individuals wasdetermined using next-generation sequencing (NGS) based CS for up to 274 genes.Detection rates were compared with literature-reported values derived fromdisease prevalence and carrier frequencies. Combined theoretical affectedpregnancy rates for the 274 screened disorders were calculated.Results: For Ashkenazi Jewish (AJ) diseases, 81.6% (4434/5435) of carriersidentified did not report AJ ancestry. For cystic fibrosis, 44.0% (6260/14,229)of carriers identified had a variant not on the standard genotyping panel.Individuals at risk of being a silent spinal muscular atrophy carrier, notdetectable by standard screening, comprised 1/39 (8763/344,407) individuals. Forfragile X syndrome, compared with standard premutation screening, AGGinterruption analysis modified risk in 83.2% (1128/1356) premutation carriers.Assuming random pairing across the study population, approximately 1/175pregnancies would be affected by a disorder in the 274-gene screeningpanel.Conclusion: Compared with standard screening, NGS-based CS provides additionalinformation that may impact reproductive choices. Pan-ethnic CS leads tosubstantially increased identification of at-risk couples. These data supportoffering NGS-based CS to all reproductive-aged women.