Clinical Genetics in Reproductive Medicine: Variant Classification, Medically Actionable Genes, and Carrier Screening

As genomic sequencing becomes more prevalent in reproductive medicine, clinicians must remain knowledgeable about the purpose of each ordered test, the principles of variant classification, and how to interpret and integrate findings into clinical decision-making. This review outlines the American College of Medical Genetics and Genomics (ACMG) standardized guidelines for sequence variant interpretation and highlights anticipated updates in the forthcoming v4.0 framework. When next-generation sequencing is performed for a clinical condition, incidental findings of pathogenic and likely pathogenic variants in medically actionable genes (MAGs) may be identified. Conditions included on the ACMG MAG list are typically highly penetrant, primarily autosomal dominant or X-linked, and have established interventions that can alter disease trajectory. Carrier screening enables the identification of autosomal recessive and X-linked variants in prospective parents that predispose them to genetic disease in their children. The ACMG's tier-based recommendations support universal Tier 3 screening, targeting conditions with a carrier frequency of at least 1 in 200 and moderate/severe phenotypes, while Tier 4 screening is reserved for individuals with consanguinity or significant family history. While technical genomic advances enhance the delivery of precision medicine, they introduce challenges, including higher rates of uncertain findings and the need for more careful clinical interpretation.