Consideration of inherited cancer risk on a continuum
Tuya Pal (Chair), Helen Hanson (Co-chair), Joseph Christopher, Will Foulkes, Paul James, Susan Klugman, Allison Kurian, Julie Mak, Alvaro Monteiro, Mark Robson, Douglas Stewart, Esteban Symonds, Marc Tischkowitz PP&G Committee
In the field of inherited cancer predisposition, the concept that risk of a specific cancer lies on a continuum (rather than based on a binary classification) of a germline pathogenic or likely pathogenic variant, is becoming increasingly important to consider. Historically, in the inherited cancer predisposition field, penetrance estimates have been anchored to genes based on ‘typical’ risks attributed through the literature. In addition, penetrance estimates have historically been ascertained “phenotype first,” meaning from families with a notable personal or family history bringing them to medical attention. Phenotypic ascertainment can inflate penetrance estimates. The ability to use the “genotype-first” approach (or genomic ascertainment) is a significant development in refining penetrance estimates. Using genes established to be associated with breast cancer as an example: from decades of primarily phenotypic ascertainment studies, BRCA1 and BRCA2 are considered to be ‘high penetrance genes’ imparting a lifetime risk of breast cancer generally in the range of 60-70%, while the ‘moderate penetrance’ CHEK2 and ATM genes are associated with a lifetime risk of breast cancer generally in the range of 20-30%. However, there are multiple factors that can impact risk. Status: Proposal is being finalized.
Cures Act and information blocking points to consider
Sara Rabin-Havt (Co-chair), Samuel Huang (Co-chair), Perry Chan, Bimal Chaudhari, Tanya Eble, Barbara Evans, Stephanie Fullerton, Jesse Hunter, Kathleen Pope SELI Committee
Pre- and post-testing counseling including results disclosure planning has long been a crucial tenet of genetic consultation. The new Office of the National Coordinator for Health Information Technology (ONC) Cures Act Final Rule, which includes provisions against information blocking, is likely to significantly impact current results disclosure practice norms. Information blocking is defined as a practice by an actor (including a healthcare provider) that is likely to interfere with access, exchange or use of health information. While this is intended to benefit patients and empower them with access to their own health information, a concerning consequence is a risk of bypassing disclosure by the healthcare team. While this risk is not unique to genetics, it does require that genetics providers consider the timing and approach to results disclosure. Even though the ONC has provided additional guidance on prohibition of information blocking and carved out 8 exceptions, the real-world implementation and intersection with clinical genomics practice remains unclear and warrants further investigation and guidance. Status: Proposal has been approved.
Points to consider: Metabolomics testing for inherited metabolic diseases
Marcus Miller (Chair), Tina Cowan, Adam Kennedy, Laura Duque Lasio, Rebecca McClellan, Devin Oglesbee, Wendy Smith, Reid Sutton Lab QA Committee
Metabolomics testing is presently being offered clinically in both the US and Europe to screen for inherited metabolic diseases. Metabolomics refers to the global detection of small molecule metabolites in a biospecimen with the goal of achieving comprehensive coverage. The final output from a metabolomics platform typically includes >1000 semiquantitative metabolite features that can be used to detect signatures of inherited metabolic diseases, uncover new diseases/biomarkers, or clarify results from other “omics” level clinical assays such as genome sequencing. Despite the promise of this emerging technology there remain many questions regarding best practices for the development and clinical application of metabolomics platforms. Contributing to this uncertainty is the fact that metabolomics methods vary substantially between laboratories both in scope of detections as well as approaches to data analysis and reporting. Status: Document in development.
Points to consider for reporting of variants in the prenatal setting
Elizabeth Spiteri (Chair), Saurav Guha (Co-chair), Vimla Aggarwal, Yassmine Akkari, Nina Gold, Nan Jiang, Leandra Tolusso Lab QA Committee
There is currently limited guidance on reporting of various types of variants on prenatal testing. The guidance that is available is often targeting a prenatal population that is referred for testing based on a pre-existing risk factor. As testing is offered to a broader population without additional risk factors reporting guidelines that are available may not be relevant. Status: Proposal is being finalized.
Points to consider for the clinical validation and implementation of optical genome mapping (AMP, CAP to be involved)
Yassmine Akkari (Chair), Vimla Aggarwal (Co-chair), Caroline Astbury, Sung-Hae (Sue) Kang, Brynn Levy, Gordana Raca, Honey Reddi, Nikhil Sahajpal, Jennifer Sanmann, Lina Shao Lab QA Committee
For an increasingly large number of constitutional and neoplastic disorders, the identification of specific numerical or structural abnormalities is often necessary for diagnosis, risk stratification and/or personalized treatment. Technological improvements coupled with the increasing need for laboratory automation and workflow optimization have fueled the interest in implementation of optical genome mapping (OGM) in clinical laboratories. OGM visualizes high molecular weight DNA allowing for an efficient evaluation of both structural and copy number aberrations of the genome in a single assay. While clinical care has traditionally relied on conventional cytogenetic studies, including G-band analysis, fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA), the emergence of OGM has allowed the detection of chromosomal aberrations, both balanced and unbalanced, in a single assay. However, due to its recent adoption into the clinical realm, there is a lack of standardization regarding validation and implementation of this technology in the clinical setting. Although several studies have been published on the clinical utility of this assay in various genomic diseases, there still exists considerable uncertainty on how to best utilize this technology in diagnostics. There is also a notable absence of standards or recommendations for clinical laboratories to validate and interpret OGM findings. Status: Proposal is being finalized.
Points to Consider for the implementation of DNA methylation arrays for clinical diagnostics (AMP, CAP to be involved)
Nan Jiang (Chair), Honey Reddi (Co-chair), Chetan Bettegowda, Jianling Ji, Marco Leung, Ditte Primdahl, Shakti Ramkissoon, Nancy Rose, Bekim Sadikovic, Lucas Santana dos Santos, Matija Snuderl, Matthew Tedder Lab QA Committee
DNA methylation is an epigenetic modification that plays an essential role in regulating gene expression, consequently exerting influence over a broad range of biological processes and diseases. For decades, methylation tests on specific gene loci or regions have been utilized primarily on the diagnosis of imprinting disorders or the detection of methylation-based cancer biomarkers. With the introduction of DNA methylation arrays, it has become feasible to quantitatively profile DNA methylation across the genome. This allows for the detection of a broader range of constitutional disorders and more precise classifications of various tumors. In recent years, DNA methylation arrays have been adopted and clinically validated for the diagnosis of both constitutional and neoplastic disorders which have aberrant DNA methylation patterns. However, there is a lack of standardization regarding validation and implementation of this technology in the clinical setting. Although several studies have been published on the clinical utility of this assay in various genomic diseases, there still exists considerable uncertainty on how to best utilize this technology in diagnostics. There is also a notable absence of standards or recommendations for clinical laboratories to interpret DNA methylation array findings. Status: Proposal is being finalized.
Points to consider for the sequencing-based detection of copy number abnormalities and chromosomal rearrangements in neoplastic disorders
Yassmine Akkari (Chair), Linda Baughn (Co-chair), Cynthia Hawkins, Nan Jiang, Ross Levine, Trevor Pugh, Gordana Raca, Kathleen Schieffer, Soheil Shams, Eliezer Van Allen Lab QA Committee
Technological improvements coupled with large cohort studies have fueled unprecedented advances in our understanding of cancer genomes. For an increasingly large number of neoplastic disorders, the identification of specific mutations, copy number abnormalities (CNAs) or chromosomal rearrangements is often necessary for diagnosis, risk stratification and/or personalized treatment. Presently, a shift in the modality through which chromosomal rearrangements and CNAs are detected and reported has emerged. While clinical care has traditionally relied on cytogenetic studies, including karyotyping, fluorescence in situ hybridization (FISH) and chromosomal microarray (CMA), next generation sequencing (NGS) data is facilitating similar analyses. However, there exists considerable variability in the design, coverage and analytical pipelines that inform NGS-driven approaches for detection of these abnormalities. Moreover, there is also a notable absence of standards or recommendations for clinical laboratories to design, validate and interpret these findings. Acquired CNAs can vary widely both in size (from small intragenic deletions and duplication to whole genome doubling events) and in copy number states (from homozygous deletions to focal, high-level amplifications); it is not uncommon that patterns of concurrent CNAs rather than individual aberrations have diagnostic or prognostic significance. Status: Document in development.
Points to consider for workplace genomic testing
Kunal Sanghavi (Co-chair), Marc Williams (Co-chair), Maria Frangenberg, Michelle McClure, Anya Prince, Laurie Seaver, Matteo Vatta, Ellen Wright Clayton SELI Committee
More than 157 million people in the US receive their healthcare insurance through employer healthplans. In some cases, employers are offering voluntary workplace genomic testing (wGT) through such health plans. Stakeholders Assessing Genetics with Employers (SAGE), a federally funded research project focused on assessing “non-indication based genetic testing” (NIBGT) provided frameworks fordemonstrating the value of NIBGT (that includes wGT) and for considering future research investments. A recent study providing an overview of vendors offering wGT reported that 53% (8/15) of vendors provided professional health or genetic consultations and only 4 vendors tested for pathogenic variants. While existing studies provide guidance for employers, our timely proposed project will inform policy makers who review the safeguards to protect privacy and confidentiality of employees, data security, and wellness programs. Status: Document in development.
Points to consider in the reporting of variants of uncertain significance in genetic and genomic testing
Heidi Rehm (Co-chair), Lora Bean (Co-chair), Aya Abu-El-Haija, Vimla Aggarwal, Yassmine Akkari, Caroline Astbury, Farid Barquet Ramos, Hunter Best, Laura Conlin, Steven Harrison, Nan Jiang, Paul Kruszka, Dianalee McKnight, Chloe Mighton, Tiffany Nguyen Dolphin, Christie Thomas Lab QA Committee
Over 30% of genetic testing reports contain a variant of uncertain significance yet physicians and patients are often ill-prepared to manage VUSs and insurers are concerned about downstream costs. Genetic testing is increasingly deployed in non-diagnostic contexts such as family history or preventive purposes with low prior probability in which case the reporting of VUS may, on balance, create more harm than good. The ACMG/AMP/CAP/ClinGen SVC v4.0 standard for sequence variant classification will soon be released and provide an easy framework for subdividing VUS by likelihood of pathogenicity. This points to consider document will provide considerations for laboratory policies in reporting of VUSs. It will cover aspects related to: clinical indication; physician and patient preferences for receiving VUSs on reports; use of the new VUS sub-tiers in reporting; use of report format strategies to influence the attention paid to VUSs. Status: Document in development.
Pre-transplant genetic testing in potential bone marrow transplant (BMT) donors: A points to consider statement from the American College of Medical Genetics and Genomics
Bryce Seifert (Chair), Lyndsey Runaas (Co-chair), Matthew Avenarius, Sarah Bannon, Yulong Fu, Nan Jiang, Ender Karaca, Sarah Rapisardo Long, Honey Reddi, Nancy Rose, Christie Thomas Lab QA Committee
For individuals with genetic disorders undergoing bone marrow transplant (BMT), siblings or close relatives are often used as donors. In the pre-transplant setting, clinicians must often choose between targeted genetic testing on the donor for the diagnostic variant(s) specific to the recipient versus more extensive genetic testing on the donor (e.g., cytogenetic testing, NGS panel, exome, or genome sequencing). This decision can be influenced by many factors. This points to consider statement will discuss the type of testing utilized in pre-transplantation settings (e.g., cytogenetic testing, single variant analysis, targeted NGS panel testing, exome/genome sequencing), genes focused on in testing potential donors (secondary findings genes and/or genes that may impact transplant success in the recipient), and whether gene content varies based on the age of potential donors (minors versus adults). Discussing these factors through a points to consider statement will better equip clinicians and clinical laboratorians in determining the optimal approach to genetic testing in potential BMT donors in the pre-transplant setting, thereby supporting the best possible BMT outcome in the recipient. Status: Proposal is being finalized.
Primer on privacy of genetic information: A points to consider statement for policymakers
Tina Hambuch-Hawks (Chair), Bob Best, Sheila Dobin, Lynn Fleisher, Marco Leung, Michelle McClure, Matt Might, Brandon Shaw, Ellen Wright Clayton AGA Committee
Privacy of genetic information is attracting a lot of attention from policymakers, including those in the US Congress. However, there seems to be little awareness regarding what genetic information is, how it is shared in clinical and research settings, and the many existing protections (such as those offered under the Common Rule and others). As a result, policies may be proposed that would have devastating unintended consequences on sharing of information for the purpose of clinical investigations or advancing medical research. For example, legislation has recently been progressing in multiple states that would override existing federal policies and require explicit consent for any use of genetic information and retention of specimens that contain genetic material regardless of deidentification. The tensions between individual control and data/sample sharing are confounded by some attributes of genetic samples and data. Further, regulations and guidelines already exist that provide conflicting information relating to the access, ownership, and use of generated genetic data. For example, there are several components of genetic data that, once generated, cannot or should not be deleted completely such as deidentified and classified variant information. Status: Document in development.
Professional application of population descriptors in clinical genetics and genomics testing and research (ClinGen to be involved)
Shuxi Liu (Chair), Jonathan Berg, Bimal Chaudhari, Teri Klein, Ana Morales, Lucilla Pizzo, Sharon Plon, Heather Samuelson, Zohreh Talebizadeh DEI Committee
The Committee on the Use of Race, Ethnicity and Ancestry as Population Descriptors in Genomics Research; National Academy of Sciences, Engineering and Medicine has published a report “Using Population Descriptors in Genetics and Genomics Research; A New Framework for an Evolving Field (2023)”. This report emphasizes the importance of accurately describing race, ethnicity, and ancestry in human genetics research. It provides suggestions on how and when to use these population descriptors effectively. However, a gap exists in the implementation and application of population descriptors in clinical genetic testing including genetic testing guidelines. This gap could introduce ambiguity and discrepancy in clinical genetics and genomics practice, genetic professional communication, coverage of genetic testing for patients as well as publication and education. Multiple areas and professionals are potentially impacted, including clinical laboratories, pharmacogenomics testing, clinical and laboratory geneticists, genetic counselors, gene and variant curators, genetic researchers, clinicians and health coverage entities and policymakers. Our proposed work aims to address this gap by providing crucial points to consider in applying and implementing the terminology of population descriptors in various genetic and genomic testing contexts, particularly those groups developing guidelines for genetic testing, diagnosis recommendation, and result interpretation. Status: Proposal is being finalized.
Regulation of laboratory-developed tests: A points to consider statement for policymakers
Marco Leung (Chair), Raymond Caylor, Olivia D’Annibale, Michelle McClure, TaraChandra Narumanchi, Laura Sack, Sarah South, Bob Wildin AGA Committee
The debate about regulation of laboratory-developed tests (LDTs) has been ongoing for nearly three decades. Currently, the primary body responsible for regulating LDTs is the Centers for Medicare and Medicaid Services (CMS) through the Clinical Laboratory Improvement Amendments (CLIA). While the US Food and Drug Administration (FDA) has the authority to regulate medical devices, it has also staked a similar – however disputed – claim that LDTs are medical devices and should be regulated as such. Despite making this claim, the FDA has typically deferred to the CMS-CLIA regulatory framework for the majority of LDTs. In recent years, however, the FDA has become more engaged and committed to the regulation of LDTs. For example, in 2019, the FDA limited how clinical laboratories could report pharmacogenetic results, and, in 2020, it required premarket reviews for all COVID-19 testing. Following this trend, the VALID Act of 2021 was proposed by congress to give the FDA authority over the regulation of a new category of test, in vitro clinical tests, which groups LDTs and manufactured test kits together for the same regulatory process and overview. Status: Document in development.
ACMG population screening: List of primary findings for reporting V1.0
Michael Murray (Co-chair), Sonja Rasmussen (Co-chair), Noura Abul-Husn, Ned Calonge, Marina DiStefano, Debra Duquette, Faith Fletcher, Muin Khoury, Bruce Korf, Murugu Manickam, Dena Matalon, Katherine Nathanson, Cynthia Powell, Maren Scheuner, Nadav Weinstock, Marc Williams ACMG Board of Directors
This proposed policy statement will use the evidence-based and criteria-driven approach described in the workgroup’s position statement to identify a minimal list of genomic variants to be prioritized by those institutions and organizations seeking to launch DNA-based population public health screening programs. It is proposed that this list be submitted for publication in GIM as version one (V1.0) of ACMG recommendations for specific genes and variants that should be assessed in order to deliver primary findings (PF) back to individuals with identified risk in population public health screening programs. Status: Document in development
Consideration of disease penetrance in the selection of secondary findings gene-disease pairs: A policy statement of the American College of Medical Genetics and Genomics (ACMG)
Noura Abul-Husn, Laura Amendola, Kyle Brothers, Wendy Chung, Michael Gollob, Adam Gordon, Steven Harrison, Ray Hershberger, Kristy Lee, Christa Lese Martin, David Miller, C. Sue Richards, Douglas Stewart ACMG Secondary Findings Working Group
Status: Document at GIM.
Use of sex and gender identifiers in clinical and laboratory genetics and genomics: A policy statement of the American College of Medical Genetics and Genomics (ACMG) (AMP, CAP to be involved)
Mahmoud Aarabi (Co-chair), Fabiola Quintero-Rivera (Co-chair), Andrea Cantor, Natario Couser, Anna Essendrup, Margo Gallegos, George Khushf, Susan Klugman, Dena Matalon, Aleksandar Rajkovic, Eric Vilain, Svetlana Yatsenko, Kimberly Zayhowski DEI and SELI Committees
Sex and gender identifiers are integral to providing patient-centered and equitable healthcare. By recognizing and respecting the differences and needs related to sex and gender, healthcare providers can deliver more effective, culturally competent, and inclusive medical care. While sex and gender are distinct, they are interconnected factors that play a significant role in determining an individual's health and healthcare needs. In genetics and genomics, it is essential to recognize the complexity of sex and gender, understand the genetic factors associated with both, and approach patient care, testing and research participation in an inclusive and respectful manner. Status: Document in development.
DNA-based population screening: Approach to gene and variant selection
Sonja Rasmussen (Co-chair), Michael Murray (Co-chair), Noura Abul-Husn, Ned Calonge, Marina DiStefano, Debra Duquette, Faith Fletcher, Muin Khoury, Bruce Korf, Murugu Manickam, Dena Matalon, Katherine Nathanson, Cynthia Powell, Maren Scheuner, Nadav Weinstock, Marc Williams ACMG Board of Directors
DNA-based approaches to population health screening have the potential to significantly improve the early detection and prevention of cancers, heart disease, and other conditions associated with identifiable genomic risk. However, a broadly applicable evidence-based approach to the selection of genes and variants for prioritization in population screening does not currently exist. Status: Document in development.
Position statement on importance of residual newborn screening dried blood spots “Update”
Nancy Rose (Chair), Julie Beans, Michele Caggana, Mary Beth Dinulos, Leslie Francis, Michele Lloyd-Puryear, Andrea Matthews, Michelle McClure, Cynthia Powell, Changrui Xiao
AGA Committee
ACMG’s position statement on the importance of residual newborn screening (NBS) dried blood spots (DBS) was developed in 2009 in response to a small but vocal group of citizens arguing for destruction of residual DBS after the screening is completed. Since then, concerns about retention of residual DBS, their use for research, consent needs, deidentification, and potential for reidentification have grown. This continues to be a topic of active discussion among state and federal policymakers. The length of time that a public health department can retain residual DBS varies significantly among states with some requiring destruction of specimens soon after screening. This is further complicated by recent lawsuits challenging state retention and use of residual DBS and related consent policies. Currently, the debate of consent for research on residual deidentified DBS has prevented reauthorization of key federal programs at the NIH, CDC, and HRSA which support state screening programs. Additionally, there have been recent reports about law enforcement in one state accessing DBS specimens from a public health laboratory to identify a suspect in a criminal investigation. Status: Document in development.
Position statement regarding resources needed to administer gene therapy
Dwight Koeberl (Co-chair), Steven Gray (Co-chair), Ali Al-Beshri, Walla Al-Hertani, Elizabeth Baker, Bronwyn Bateman, Natario Couser, Ed Esplin, Jaya Ganesh, Brett Graham, Julie Lander, Nicola Longo, Loren Peña, Claudia Soler-Alfonso, Jerry Vockley Therapeutics Committee
The question to be addressed by this Position Statement is “what resources are needed to participate in gene therapy clinical trials and deliver it in clinical practice?”. The output will be a “Checklist of Gene Therapy Infrastructure” that will be relevant to facilities that are responsible for gene therapy product acquisition, storage and administration. The need for this Statement is urgent, since gene therapy is a novel and expanding modality of treatment that has unique requirements for delivery that differ from previous therapies such as small molecule drugs or enzyme replacement therapies. Furthermore, medical geneticists are already involved in the development and delivery of gene therapy, and should make recommendations regarding the needs for infrastructure to support it. This project represents follow-up to an expert panel convened by the National Organization for Rare Disorders (NORD) to address topics related to rare disorder therapies. Status: Document in development.
Laboratory guideline for Turner syndrome “Update”
Vimla Aggarwal (Co-chair), Yassmine Akkari (Co-chair), Nan Jiang, Lauren Mohnach, Joie Olayiwola, Jennifer Sanmann, Teresa Smolarek, Daynna Wolff
Turner syndrome is a disorder of sex development with distinct clinical features and cytogenetic findings. In 2010, the ACMG Lab QA published a laboratory guideline for Turner syndrome (PMID: 20081420). These guidelines were re-affirmed in 2014. Although many guidelines have been published on the clinical management of this disorder, the ACMG publication remains, to date, one of the few guidelines on the cytogenetic workup of Turner syndrome. Herein, we propose an update of the 2010 guidelines and present new information regarding the diagnostic workup of this syndrome whenever applicable. Status: Proposal is being finalized.
Interpreting sequence variants: A joint consensus statement of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology “Update”
Les Biesecker (Co-chair), Steven Harrison (Co-chair), Ahmad Abou-Tayoun, Jonathan Berg, David Bick, Alicia Byrne, Elizabeth Chao, Sian Ellard, Julie Gastier-Foster, Izabella Karbassi, Heather McLaughlin, Ann Moyer, Anne O'Donnell-Luria, Sharon Plon, Heidi Rehm, Sue Richards, Lisa Vincent, Nicky Whiffin
Revision of ACMG Interpreting Sequence Variation Guideline: Revise current guideline to address ambiguities in some criteria as well as appropriateness and strength of other criteria; Develop mechanism for ongoing guideline addenda and to include gene-specific modifications from ClinGen Expert Panels as approved by the ClinGen SVI; Include recommendation on which variants are appropriate for use in varying clinical intended uses (e.g., diagnostic testing vs. screening otherwise healthy individuals); Consider establishing quantitative parameters for criteria; Accept updates from ClinGen SVI every 6 months to plan for and develop additional addenda. Status: Document in development.
Isolated asymmetric overgrowth: A practical guide for diagnosis and management
Angelika Erwin (Co-chair), Jennifer Kalish (Co-chair), Aya Abu-El-Haija, James Bennett, Leslie Biesecker, Matthew Deardorff, Marilyn Li, Julian Martinez, Michael Walsh
Asymmetric overgrowth (AO) is characterized by increased tissue growth in any part of the body. Affected tissues can include bone, muscle, connective tissue, and vasculature. AO can be associated with syndromic overgrowth syndromes but can also occur as isolated lateralized overgrowth. For the well-described overgrowth syndromes including Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum, Proteus syndrome, and PTEN hamartoma tumor syndrome an increased but varied tumor risk is known and, in some cases, periodic screening for neoplasms is recommended. These overgrowth syndromes are caused by genetic or epigenetic defects that can occur in a mosaic or somatic form, which means they may not be detectable in a blood sample and molecular evaluation of an affected tissue type may be necessary to establish the correct molecular diagnosis. Status: Document in development.
Management of germline pathogenic variation in ATM: A practical guide
Tuya Pal (Co-chair), Marc Tischkowitz (Co-chair), Esteban Astiazaran Symonds, Judith Balmaña, William Foulkes, Helen Hanson, Paul James, Susan Klugman, Julie Mak, Joanne Ngeow, Rita Schmutzler, Katherine Schon, Douglas Stewart, Nicoleta Voian, Myra Wick
ATM is considered a moderate penetrance gene with pathogenic variants with a relatively high frequency in the population. Consequently, it is important to develop consensus and a framework for the use of cancer-risk management strategies based on cancer risks in conjunction with age distribution and other potential modifying factors. Furthermore, there are specific genotype and phenotype considerations, including a high penetrance pathogenic variant in ATM (c.7271T>G) which may warrant specific consideration. Additionally, the complexity is further heightened given that bi-allelic ATM P/LP variants lead to ataxia-telangiectasia, a childhood onset cancer-predisposing condition which predisposes to radiation sensitivity prompting evaluation and misinformation about radiation sensitivity in heterozygotes. Status: Document in development.
Management of individuals with germline pathogenic/likely pathogenic variants in BRIP1/RAD51C/RAD51D
Helen Hanson (Co-chair), Joanne Ngeow (Co-chair), Douglas Stewart (Co-chair), Esteban Astiazaran Symonds, Judith Balmaña, Ilana Cass, Jianbang Chiang, William Foulkes, Paul James, Arielle Katcher, Susan Klugman, Felix Kommoss, Julie Mak, Tuya Pal, Marc Tischkowitz, Nicoleta Voian, Myra Wick
BRIP1, RAD51C and RAD51D, are considered as moderate penetrance ovarian cancer predisposition genes. Whilst risk reducing bilateral salpingo—oophorectomy is considered standard of care for high risk ovarian cancer risk genes, recommendations for BRIP1, RAD51C and RAD51D are more nuanced as risk is largely conferred after age 50 and therefore the risk-benefit of an early surgical menopause needs to be carefully balanced with age specific and lifetime risks. It is therefore important to develop consensus and a framework for cancer risk management strategies based on cancer risks in conjunction with age distribution and other potential modifying factors such as family history. Furthermore, there has historically been conflicting data on the association of these genes with breast cancer risk, but recent large case control studies have provided more robust evidence that RAD51C and RAD51D are associated with breast cancer predisposition, whilst BRIP1 is not. Status: Proposal is in development.
ACMG/CAP technical standards for prenatal cell-free DNA screening
Erin Wakeling (Co-chair), Ross Rowsey (Co-chair), Sucheta Bhatt, Phillip Cacheris, Benjamin Hilton, Sung-Hae (Sue) Kang, Edward Kloza, Brynn Levy, Bryce Seifert, Shashirekha Shetty
Historically, prenatal screening for common chromosomal aneuploidies involved maternal age assessment, measurements of maternal serum analytes and/or ultrasonography. Advances in genomic technologies, such as next generation sequencing, led to prenatal cell-free DNA screening of placenta-derived cell-free DNA present in the maternal blood to identify fetuses at increased risk of Trisomy 13, 18 and 21 and aneuploidy of sex chromosomes. Since its introduction in 2009, prenatal cell-free DNA screening has achieved rapid clinical acceptance and is currently the most sensitive and specific screening test for the common chromosomal aneuploidies. Status: Document in development.
Biochemical testing for congenital disorders of glycosylation: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Patricia Hall (Chair), Andrew Edmondson, Christina Lam, Kimiyo Raymond, Lynne Wolfe
The clinical and laboratory spectra of glycosylation disorders are expanding rapidly as more and more disorders are identified and linked to glycosylation pathways. Laboratory testing for glycosylation disorders has been centered around the analysis of carbohydrate deficient transferrin analysis, with confirmatory enzyme analysis for many years. In the past 10 years, high-resolution mass spectrometry has allowed for additional information to be obtained. These techniques have identified new glycosylation disorders and expanded to include ancillary techniques, such as urine oligosaccharide screening and flow cytometry where specific profiles can be diagnostic. Interpretation of biochemical genetic testing for glycosylation disorders is complex, as for many disorders only a small number of patients have been identified. Understanding the technical and clinical limitations (including false positive and false negative results) for glycosylation techniques will be beneficial for laboratorians and clinicians. This proposed technical laboratory standard for biochemical genetic testing for congenital disorders of glycosylation will focus on transferrin analysis, glycan profiling and enzyme analysis and is an opportunity to pull together information that has previously not been presented in a comprehensive and unified manner. Status: In subcommittee review.
Biomarker testing for lysosomal diseases: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Ashlee Stiles (Chair), Taraka Donti, Patricia Hall, William Wilcox
A hallmark of lysosomal storage disorders is the accumulation of toxic substrates as a result of enzymatic deficiency. Recent advances have allowed for detection of these analytes using liquid chromatography-tandem mass spectrometry based techniques. Furthermore, biomarker analysis has been incorporated in the diagnostic work-up and clinical monitoring of patients with lysosomal storage disorders on treatment as a way to determine compliance and patients’ response to treatment. As laboratories begin to offer these tests clinically, a laboratory technical standard will provide a general reference for the measurement and interpretation of biomarker results for patients on treatment with Fabry, Gaucher, and Pompe disease. We have chosen to focus on these three lysosomal storage disorders in particular due to their prevalence, therapeutic potential and those already included in the Recommended Uniform Screening Panel for newborn screening. Fabry and Gaucher disease are sphingolipidoses and result from enzymatic deficiency in the globoside degradation pathway. Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency and results in the accumulation of globotriaosylceramide (Gb3) in urine as well as lyso-Gb3 in plasma. Gaucher disease is an autosomal recessive disorder that results from β-glucosidase deficiency and results in the accumulation of glucosylsphingosine (GlcSph) in tissues. Status: Posted for member comment.
Laboratory testing for preconception/prenatal carrier screening: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Saurav Guha (Co-chair), Honey Reddi (Co-chair), Mahmoud Aarabi, Marina DiStefano, Jeffrey Dungan, Anthony Gregg, Erin Wakeling
Carrier screening has historically assessed a relatively small number of autosomal recessive and X-linked conditions selected based on frequency in a specific subpopulation and association with severe morbidity or mortality. Rapid changes in genomic technologies now enable screening all individuals for dozens to hundreds of autosomal recessive and X-linked conditions, some with lower frequencies or severity grades, typically without tailoring to a person’s reported ethnicity and share the same objective as traditional carrier screening — to inform couples of their risks so that they may consider reproductive options. Status: Document at GIM.
Myotonic dystrophy type 1 testing, 2024 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Bryce Seifert (Co-chair), Honey Reddi (Co-chair), Lora Bean, Benjamin Kang, Nancy Rose, Amy Shealy
In consultation with Dr. Tom Prior, the previous author of this Technical Standard, revisions to methodology as well as nomenclature are needed to update the previous Technical standards and guidelines for myotonic dystrophy type 1 testing. Status: Document at GIM.
Prenatal screening for Down syndrome (trisomy 21) using first- and second-trimester biochemistry and ultrasound measurements: A technical standard of the American College of Medical Genetics and Genomics (ACMG)
Robert Best (Chair), Glenn Palomaki (Co-chair), Komal Bajaj, Anna Chesson Hurst, Geralyn Messerlian, Ross Rowsey, Wendy Smith
This is a proposed update of a Technical Standards and Guidelines document written in 2009 and focused on prenatal screening for Down syndrome using age, maternal serum biochemical markers and ultrasound that will be expanded to include circulating cell free DNA. We propose to consolidate with the most current document that addresses second trimester Down syndrome screening as well (2005; "Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories"). Status: Document in revision.
Section E9 of the ACMG Technical Laboratory Standards for fluorescence in situ hybridization (FISH)
Sung-Hae (Sue) Kang (Co-chair), Karen Tsuchiya (Co-chair), Yassmine Akkari, Julia Bridge, Andrew McFaddin, Lucilla Pizzo, Jennifer Sanmann, Lina Shao
This document represents a proposed update of Section E9 of the ACMG technical standards and guidelines: Fluorescence in situ hybridization (FISH), which was originally published in 2011 and reaffirmed in 2018. In October 2021, the Cytogenetics Lab QA subcommittee convened and agreed on updating this document to reflect current practices, and address challenges in validations and in the establishment of reference ranges. The project will be in collaboration with the CAP Cytogenetics Committee. Status: Document in development.
Technical standards and guidelines for venous thromboembolism testing (Factor V Leiden and prothrombin 20210G>A testing), 2024 revision
Benjamin Kang (Chair), Saurav Guha (Co-chair), Hunter Best, Jeffrey Dungan, Harry Lesmana, Kara Reynolds, Shulin Zhang
Based on the ACMG Laboratory Quality Assurance Molecular Subcommittee discussion, all the subcommittee members agreed that two minor revisions are needed to update the previous technical standards and guidelines for venous thromboembolism testing. Status: Proposal is being finalized.
Technical standards for the interpretation and reporting of constitutional copy-number variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) “Update” (AMP, CAP to be involved)
Erin Rooney Riggs (Co-chair), Erik Thorland (Co-chair), Erica Anderson, John Herriges, Anne Higgins, Sung-Hae (Sue) Kang, Christa Lese Martin, Chelsea Lowther, Brynn Levy, Ludmila Matyakhina, Dominic McMullen, Daniel Pineda Alvarez, Lina Shao, Shashirekha Shetty, Andrea Vaags
The goal of this project is to update and revise the 2020 ACMG/ClinGen technical standards for interpretation and reporting of constitutional copy number variants (CNVs). Status: Document in development.
Technical standard for mucopolysaccharidoses metabolite testing
Anna Scott (Chair), Maria Descartes, Patricia Dickson, Marzia Pasquali, Dawn Peck, Sarah Young, Chelsea Zimmerman
Newborn screening programs are expanding to include lysosomal storage disorders (LSDs), raising awareness for these diseases and increasing demand for follow-up diagnostic testing. The availability of new therapies also requires accurate monitoring of disease status through analysis of specific biomarkers. The mucopolysaccharidoses (MPS) are a subset of LSDs that are characterized by accumulation of glycosaminoglycans (GAGs). New methodologies for analyzing GAGs and related analytes, especially those utilizing liquid chromatography-mass spectrometry (LC-MS/MS), are becoming increasingly widespread for the diagnosis and monitoring of patients with these disorders. However, different methods are used and there is no standardization regarding the use of internal standards, calibration material, and quality controls. This standard will focus on GAG testing and is intended to provide guidance on a standardized approach to test validation, independently from the method used. The document will educate clinicians and laboratorians about testing options with an emphasis on assay limitations and benefits. This standard will complement a document that is in progress describing lysosomal enzyme testing. Status: Document in development.
Cytogenetics defined: A technology-agnostic science for the detection of chromosomal aberrations in disease
Jennifer Sanmann (Chair), Vimla Aggarwal, Yassmine Akkari, Nan Jiang, Sung-Hae (Sue) Kang, Joie Olayiwola, Gordana Raca, Lina Shao, Elizabeth Spiteri
A significant number of constitutional and neoplastic disorders benefit from the identification of specific numerical and/or structural chromosomal abnormalities for appropriate diagnosis, risk stratification, and/or targeted therapy. As a result, the utilization of genetic testing that can provide this type of information is on the rise across the medical community, with ordering providers ranging from general practitioners to highly specialized genetics professionals. Simultaneously, the tools and technologies used to generate this clinically-relevant genetic information are evolving at a rapid pace. Examples of emerging technologies that provide insight into copy number and structural chromosomal aberrations include optical genome mapping and genome sequencing. Status: Proposal is being finalized.
Laboratory considerations for Hg37 to Hg38 reference transition
Lora Bean (Chair), Vimla Aggarwal, Saurav Guha, Matthew Lebo, Curt Scharfe
Bioinformatics pipelines developed and/or validated by clinical laboratories using the Hg37 reference sequence are unlikely to have previously migrated the reference sequence. Therefore, laboratories have no previous validation scheme to fully address all functionality of the pipeline. The complexity of genomic data and the software systems that manage that data make design of a comprehensive validation plan for changing a core feature challenging. Status: Proposal is being finalized.
Technical standards for the reporting and sharing of interpreted genomic variation: Guidance for journals and authors from ACMG, AMP, ASHG, CAP, CCMG, and HUGO
Hunter Best (Chair), Matt Avenarius, Lora Bean, George Burghel, Sara Cullinan, Laura Conlin, Isabelle De Bie, Fei Dong, Peter Freeman, Jordan Lerner-Ellis, Marco Leung, Jennifer Posey, Heidi Rehm, Somak Roy, James Solomon, Elizabeth Spiteri, Robert Steiner, Rachel Taylor
Variation in the sequence of the human genome is the basis of heritable (germline) disorders or may lead to a predisposition to non-heritable (somatic) disorders such as cancer. Proper documentation of sequence variation is critical in aiding in the clinical care of patients and also in the performance research studies. As such, accuracy in the description of reported sequence variants is of the utmost importance. Although HGVS nomenclature guidelines are widely accepted in the field of genetics, many journals do not adhere to these guidelines resulting in discrepant naming of identified/reported variants. This can directly impact clinical variant interpretation and therefore patient diagnosis/management. A technical standards document aimed at standardizing reporting variants across all major publishers would help to ensure that identified variants are correctly cataloged in variant databases. In turn this will help clinical laboratorians to accurately interpret rare variants identified in clinical genomic sequencing. Status: Document in development.
Trofinetide (Daybue)
Carlos Mares Beltran, Andres Morales Corado, Pavalan Panneer Selvam, Kuntal Sen
This document will contain a brief update on the newly FDA-approved treatment, trofinetide (trade name: Daybue). This is an oral medication that has been approved for individuals 2 years and older with Rett syndrome. Status: Document in development.
Exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia)
Andres Morales Corado, Sun Young Kim, Harry Lesmana, Sheri Poskanzer
This document will contain a brief update on the newly FDA-approved treatment, exagamglogene autotemcel (Casgevy). This is an intravenous autologous genome edited hematopoietic stem-cell based gene therapy approved for individuals 12 years and older with sickle cell disease (SCD) and recurrent vaso-occlusive crises. Additionally, the document will provide a brief update on the simultaneously FDA-approved treatment, lovotibeglogene autotemcel (Lyfgenia). This is an intravenous autologous hematopoietic stem cell-based gene therapy indicated for the treatment of patients 12 years and older with SCD and vaso-occlusive crises. Status: Document in development.