{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T23:24:30Z","timestamp":1775690670984,"version":"3.50.1"},"reference-count":46,"publisher":"Georg Thieme Verlag KG","issue":"04","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Semin Reprod Med"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1055\/a-2781-8392","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T00:06:19Z","timestamp":1773792379000},"page":"243-253","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Genetics in Reproductive Medicine: Variant Classification, Medically Actionable Genes, and Carrier Screening"],"prefix":"10.1055","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6972-1952","authenticated-orcid":false,"given":"Anastasia","family":"Navitski","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence C.","family":"Layman","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Medical College of Georgia at Augusta University, Augusta, Georgia"},{"name":"Section of Reproductive Endocrinology, Infertility, and Genetics, Medical College of Georgia at Augusta University, Augusta, Georgia"},{"name":"Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"issue":"05","key":"ref1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"08","key":"ref2","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/s41436-021-01172-3","article-title":"ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"D T Miller","year":"2021","journal-title":"Genet Med"},{"issue":"07","key":"ref3","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/gim.2013.73","article-title":"ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing","volume":"15","author":"R C Green","year":"2013","journal-title":"Genet Med"},{"issue":"02","key":"ref4","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/gim.2016.190","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics","volume":"19","author":"S S Kalia","year":"2017","journal-title":"Genet Med"},{"issue":"03","key":"ref5","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"M Kircher","year":"2014","journal-title":"Nat Genet"},{"issue":"10","key":"ref7","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1002\/humu.24088","article-title":"Fitting a naturally scaled point system to the ACMG\/AMP variant classification guidelines","volume":"41","author":"S V Tavtigian","year":"2020","journal-title":"Hum Mutat"},{"issue":"09","key":"ref8","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/gim.2017.210","article-title":"Modeling the ACMG\/AMP variant classification guidelines as a Bayesian classification framework","volume":"20","author":"S V Tavtigian","year":"2018","journal-title":"Genet 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report-a technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"22","author":"L JH Bean","year":"2020","journal-title":"Genet Med"},{"issue":"01","key":"ref14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/gim.2017.69","article-title":"Systematic design and comparison of expanded carrier screening panels","volume":"20","author":"K A Beauchamp","year":"2018","journal-title":"Genet Med"},{"issue":"11","key":"ref15","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: the human genomic variant search engine","volume":"35","author":"C Kopanos","year":"2019","journal-title":"Bioinformatics"},{"issue":"02","key":"ref16","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/cge.14516","article-title":"Genebe.net: Implementation and validation of an automatic ACMG variant pathogenicity criteria assignment","volume":"106","author":"P Stawi\u0144ski","year":"2024","journal-title":"Clin Genet"},{"issue":"11","key":"ref17","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1002\/humu.23631","article-title":"Evidence-based assessments of clinical actionability in the context of secondary findings: updates from ClinGen's Actionability Working Group","volume":"39","author":"E M Webber","year":"2018","journal-title":"Hum Mutat"},{"issue":"08","key":"ref18","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/s41436-021-01171-4","article-title":"Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"D T Miller","year":"2021","journal-title":"Genet Med"},{"issue":"07","key":"ref19","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/j.gim.2022.04.006","article-title":"ACMG SF v3.1 list for reporting of secondary findings in clinical 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Saeidian","year":"2024","journal-title":"Genet Med"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1111\/ahg.12586","article-title":"Secondary findings in 443 exome sequencing data","volume":"89","author":"M Brankovi\u0107","year":"2025","journal-title":"Ann Hum Genet"},{"issue":"07","key":"ref33","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1093\/humrep\/deac100","article-title":"Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management","volume":"37","author":"L Kasak","year":"2022","journal-title":"Hum Reprod"},{"issue":"04","key":"ref35","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.ajhg.2025.02.018","article-title":"Actionable genetic variants in 4,198 Scottish participants from the Orkney and Shetland founder populations and implementation of return of results","volume":"112","author":"S M Kerr","year":"2025","journal-title":"Am J Hum 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severity for evaluation of expanded carrier screening panels","volume":"9","author":"G A Lazarin","year":"2014","journal-title":"PLoS One"},{"issue":"07","key":"ref45","doi-asserted-by":"crossref","first-page":"101137","DOI":"10.1016\/j.gim.2024.101137","article-title":"Laboratory testing for preconception\/prenatal carrier screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG)","volume":"26","author":"S Guha","year":"2024","journal-title":"Genet Med"},{"issue":"03","key":"ref46","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1097\/AOG.0000000000000666","article-title":"Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine","volume":"125","author":"J G Edwards","year":"2015","journal-title":"Obstet Gynecol"},{"issue":"10","key":"ref47","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1200\/JCO.2016.71.0012","article-title":"Cancer susceptibility gene mutations in individuals with colorectal cancer","volume":"35","author":"M B Yurgelun","year":"2017","journal-title":"J Clin Oncol"},{"issue":"05","key":"ref48","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cardfail.2018.03.004","article-title":"Genetic evaluation of cardiomyopathy-a Heart Failure Society of America Practice guideline","volume":"24","author":"R E Hershberger","year":"2018","journal-title":"J Card Fail"},{"issue":"02","key":"ref49","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ajhg.2023.01.001","article-title":"Comprehensive SMN1 and SMN2 profiling for spinal muscular atrophy analysis using long-read PacBio HiFi sequencing","volume":"110","author":"X Chen","year":"2023","journal-title":"Am J Hum 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