ACMG Statements and Guidelines
These online statements and guidelines are definitive and may be cited using the digital object identifier (DOI). These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical genetics services; they should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. Please refer to the leading disclaimer in each document for more information.
Addendum: Technical standards and guidelines: Molecular genetic testing for ultra-rare disordersThis document was retired by the American College of Medical Genetics and Genomics (ACMG) Board of Directors as of May 20, 2019 with the following addendum.
Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG)To develop an evidence-based clinical practice guideline for the use of exome and genome sequencing (ES/GS) in the care of pediatric patients with one or more congenital anomalies (CA) with onset prior to age 1 year or developmental delay (DD) or intellectual disability (ID) with onset prior to age 18 years.
Direct-to-consumer prenatal testing for multigenic or polygenic disorders: a position statement of the American College of Medical Genetics and Genomics (ACMG)A correction to this article is available online at https://doi.org/10.1038/s41436-021-01275-x .
Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology.
Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)Chromosomal microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism array, are widely applied in the diagnostic evaluation for both constitutional and neoplastic disorders. In a constitutional setting, this technology is accepted as the first-tier test for the evaluation of chromosomal imbalances associated with intellectual disability, autism, and/or multiple congenital anomalies. Furthermore, chromosomal microarray analysis is recommended for patients undergoing invasive prenatal diagnosis with one or more major fetal structural abnormalities identified by ultrasonographic examination, and in the evaluation of intrauterine fetal demise or stillbirth when further cytogenetic analysis is desired.
Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited.
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)A correction to this article is available online at https://doi.org/10.1038/s41436-021-01278-8 .
Incidental detection of acquired variants in germline genetic and genomic testing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG)With recent advances in DNA sequencing technology, it is now possible to begin to appreciate the full scope of DNA variation that arises over the course of an individual’s lifetime.1,2 Our understanding of how the human genome changes over time and in response to external exposures is growing with the improved availability of next-generation sequencing (NGS) based testing, including exome/genome sequencing of large patient cohorts. Clinical laboratories employing NGS-based methodologies can detect many types of DNA sequence variation including those that are present at a reduced variant allele fraction (VAF) (i.e., less than the 50% expected for a heterozygous germline finding).
DNA-based screening and population health: a points to consider statement for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG)A comment to this article is available online at https://doi.org/10.1038/s41436-021-01141-w .
DNA-based screening and personal health: a points to consider statement for individuals and health-care providers from the American College of Medical Genetics and Genomics (ACMG)A comment to this article is available online at https://doi.org/10.1038/s41436-021-01141-w .
Focused Revision: ACMG practice resource: Genetic evaluation of short statureAddendum to: “ACMG practice guideline: Genetic evaluation of short stature”. Laurie H. Seaver, MD and Mira Irons, MD; ACMG Professional Practice and Guidelines Committee Genetics in Medicine 11:465–470 (2009); https://doi.org/10.1097/GIM.0b013e3181a7e8f8 ; published online 02 April 2009.
Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG)Molecular genetic testing of the FMR1 gene is commonly performed in clinical laboratories. Pathogenic variants in the FMR1 gene are associated with fragile X syndrome, fragile X–associated tremor ataxia syndrome (FXTAS), and fragile X–associated primary ovarian insufficiency (FXPOI). This document provides updated information regarding FMR1 pathogenic variants, including prevalence, genotype–phenotype correlations, and variant nomenclature. Methodological considerations are provided for Southern blot analysis and polymerase chain reaction (PCR) amplification of FMR1, including triplet repeat–primed and methylation-specific PCR.
Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG)Acylcarnitine analysis is a useful test for identifying patients with inborn errors of mitochondrial fatty acid β-oxidation and certain organic acidemias. Plasma is routinely used in the diagnostic workup of symptomatic patients. Urine analysis of targeted acylcarnitine species may be helpful in the diagnosis of glutaric acidemia type I and other disorders in which polar acylcarnitine species accumulate. For newborn screening applications, dried blood spot acylcarnitine analysis can be performed as a multiplex assay with other analytes, including amino acids, succinylacetone, guanidinoacetate, creatine, and lysophosphatidylcholines.
Addendum: ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testingThis is an addendum to the article available online at https://doi.org/10.1038/gim.2012.165 .
Addendum: Statement on nutritional supplements and piracetam for children with Down syndromeThe original statement was published in the ACMG newsletter in 1996.
Addendum: Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalitiesAddendum to: Genetics in Medicine 12:742–745 (2010) https://doi.org/10.1097/GIM.0b013e3181f8baad , published online 18 October 2010.
Addendum: American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardationAddendum to: Genetics in Medicine7:650–654 (2005); https://doi.org/10.1097/01.gim.0000186545.83160.1e , published online 01 November 2005
Treatment of mucopolysaccharidosis type II (Hunter syndrome): a Delphi derived practice resource of the American College of Medical Genetics and Genomics (ACMG)Mucopolysaccharidosis, type II (MPS II, MIM 309900) is a severe lysosomal storage disease with multisystem involvement. There is one product approved by the FDA, an enzyme replacement therapy, based on a phase III trial in older, attenuated MPS II individuals. Guidance on treatment of MPS II is lacking, not only in general, but for specific clinical situations. A previous systematic evidence-based review of treatment for MPS II demonstrated insufficient strength in all data analyzed to create a definitive practice guideline based solely on published evidence.
The interface of genomic information with the electronic health record: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG)Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
Points to consider when assessing relationships (or suspecting misattributed relationships) during family-based clinical genomic testing: a statement of the American College of Medical Genetics and Genomics (ACMG)Trio-based genetic analysis (typically involving a child and their biological parents) is an important tool in clinical diagnostic testing, as this type of analysis aids in developing an accurate understanding of the inheritance of variants observed in the proband.1-5 Understanding if a variant is inherited or is de novo can directly affect variant classification and result interpretation; consequently, misunderstanding the true biological relationship between analyzed samples can lead to erroneous clinical interpretations.
CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG)Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods.
Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG)In 1980, Eric Engel1 first proposed the concept of uniparental disomy (UPD), in which both homologous chromosomes are inherited from one parent, with no contribution (for that chromosome) from the other parent. In 1988, the first case of a Mendelian disorder associated with UPD was reported, in which a child with cystic fibrosis (MIM 219700) had inherited two copies of a pathogenic variant in CFTR (MIM 602421) from a heterozygous carrier mother, with no contribution from the biological father.2
Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG)The sequencing of tumor-derived DNA to identify tumor-specific variations (biomarkers) with potential diagnostic, prognostic, or predictive therapeutic implications (hereafter, “tumor testing”) is a prominent example of precision medicine. Although the primary goal of this testing is the identification of biomarkers to guide patient management, testing tumor genomes also has the potential to uncover clinically relevant germline variation that is associated with heritable cancer susceptibility and other conditions, and carrier status for autosomal recessive disorders, if confirmed to be present in the germline.
Risk categorization for oversight of laboratory-developed tests for inherited conditions: an updated position statement of the American College of Medical Genetics and Genomics (ACMG)This document represents an update to the proposed approach of the American College of Medical Genetics and Genomics (ACMG) to categorize laboratory-developed tests (LDTs) for inherited conditions according to risk.1 Risk classification has historically been a determinant of whether, and to what extent, the US Food and Drug Administration (FDA) has overseen and regulated clinical tests. LDTs for constitutional variants continue to proliferate without a comprehensive federal regulatory framework in place.
Systematic evidence-based review: outcomes from exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disabilityExome and genome sequencing (ES/GS) are performed frequently in patients with congenital anomalies, developmental delay, or intellectual disability (CA/DD/ID), but the impact of results from ES/GS on clinical management and patient outcomes is not well characterized. A systematic evidence review (SER) can support future evidence-based guideline development for use of ES/GS in this patient population.