ACMG recommendations for standards for interpretation of sequence variations

Kazazian, Jr; Boehm, Carola; Seltzer, W. K.

doi:10.1097/00125817-200009000-00009

Cited by 72 publications

(9 citation statements)

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“…The original 2000 guidelines established five categories of classifications but provided little guidance on evidence selection and weighting. 3 Revision of these guidelines in 2007 incorporated a sixth category of variants: those associated with clinical symptoms, but that are unexpected or unknown to cause disease (e.g. risk variants).…”

Section: Overview Of Acmg/amp Sequence Variant Interpretation Guidelinesmentioning

confidence: 99%

“…In lieu of formal statistical approaches, significant efforts have been made to develop guidelines describing the evidence types needed to assess variants implicated in Mendelian diseases. 3–5 In this review, we focus on the evidence types articulated by the clinical genetics community as providing support for or against pathogenicity of a variant with respect to a monogenic disorder, and the nuances inherent in combining the available evidence to arrive at a clinical interpretation. Accurate variant interpretations often warrant the expertise of a trained molecular geneticist.…”

Section: Introductionmentioning

confidence: 99%

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Navigating the nuances of clinical sequence variant interpretation in Mendelian disease

Strande

Brnich

Roman

et al. 2018

Genetics in Medicine

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Understanding clinical genetic test results in the era of next-generation sequencing has become increasingly complex, necessitating clear and thorough guidelines for sequence variant interpretation. To meet this need the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for a systematic approach for sequence variant interpretation in 2015. This framework is intended to be adaptable to any Mendelian condition, promoting transparency and consistency in variant interpretation, yet its comprehensive nature yields important challenges and caveats that end users must understand. In this review, we address some of these nuances and discuss the evolving efforts to refine and adapt this framework. We also consider the added complexity of distinguishing between variant-level interpretations and case-level conclusions, particularly in the context of the large gene panel approach to clinical diagnostics.

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Section: Overview Of Acmg/amp Sequence Variant Interpretation Guidelinesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Navigating the nuances of clinical sequence variant interpretation in Mendelian disease

Strande

Brnich

Roman

et al. 2018

Genetics in Medicine

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“…College of Medical Genetics Recommendations for Laboratory Standards for Interpretation of Sequence Variants (Kazazian et al, 2000), and are discussed here.…”

Section: 1611mentioning

confidence: 99%

“…If mutations are found that are not on the available Web sites, or are listed as unknown, standard approaches to assessing and reporting the pathogenicity of variants must be taken. An overview of these issues and approaches is outlined in the American College of Medical Genetics Recommendations for Laboratory Standards for Interpretation of Sequence Variants (Kazazian et al, ), and are discussed here.…”

Section: Guide To Data Interpretationmentioning

confidence: 99%

Molecular Diagnosis of Hearing Loss

Rehm¹

2004

CP Human Genetics

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This unit discusses an approach to identifying a genetic cause in an individual with nonsyndromic hearing loss. Two protocols are presented, including a full-gene sequencing assay to identify mutations in the GJB2 gene encoding the connexin 26 protein. Mutations in the GJB2 gene represent the most common cause of congenital hearing loss. In addition, a protocol to detect the presence of a 342-kb deletion that includes a portion of the GJB6 gene is presented. The GJB6-D13S1830 deletion, in homozygosity or in combination with a single GJB2 mutation, causes hearing loss. In addition to the two protocols presented, the Strategic Planning section presents a discussion of a decision-making process that can be used to begin determining which gene(s) to test for in a patient presenting with nonsyndromic hearing loss. This task can be quite challenging, with the suspected involvement of over 90 genes.

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“…To address this challenge, in 2008 and, again, 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) revised and updated its original guidelines [ 1 , 2 ] for the interpretation of sequence variants identified through genomic testing in patients with suspected inherited Mendelian disorders [ 3 ]. These guidelines recommend the use of a five-tier system of classification for sequence variants (pathogenic, likely pathogenic, uncertain significance (VUS), likely benign, and benign) and provide a set of 28 criteria that organize the available levels of information (i.e., population data, computational and predictive data, functional data, segregation data, and other).…”

Section: Introductionmentioning

confidence: 99%

Variant Selection and Interpretation: An Example of Modified VarSome Classifier of ACMG Guidelines in the Diagnostic Setting

Cristofoli¹,

Sorrentino²,

Miotto³

et al. 2021

Genes

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Variant interpretation is challenging as it involves combining different levels of evidence in order to evaluate the role of a specific variant in the context of a patient’s disease. Many in-depth refinements followed the original 2015 American College of Medical Genetics (ACMG) guidelines to overcome subjective interpretation of criteria and classification inconsistencies. Here, we developed an ACMG-based classifier that retrieves information for variant interpretation from the VarSome Stable-API environment and allows molecular geneticists involved in clinical reporting to introduce the necessary changes to criterion strength and to add or exclude criteria assigned automatically, ultimately leading to the final variant classification. We also developed a modified ACMG checklist to assist molecular geneticists in adjusting criterion strength and in adding literature-retrieved or patient-specific information, when available. The proposed classifier is an example of integration of automation and human expertise in variant curation, while maintaining the laboratory analytical workflow and the established bioinformatics pipeline.

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ACMG recommendations for standards for interpretation of sequence variations

Cited by 72 publications

References 0 publications

Navigating the nuances of clinical sequence variant interpretation in Mendelian disease

Navigating the nuances of clinical sequence variant interpretation in Mendelian disease

Molecular Diagnosis of Hearing Loss

Variant Selection and Interpretation: An Example of Modified VarSome Classifier of ACMG Guidelines in the Diagnostic Setting

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