ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007

Abstract

ACMG previously developed recommendations for standards for interpretation of sequence variations. We now present the updated revised recommendations. Here, we describe six interpretative categories of sequence variations: (1) sequence variation is previously reported and is a recognized cause of the disorder; (2) sequence variation is previously unreported and is of the type which is expected to cause the disorder; (3) sequence variation is previously unreported and is of the type which may or may not be causative of the disorder; (4) sequence variation is previously unreported and is probably not causative of disease; (5) sequence variation is previously reported and is a recognized neutral variant; and (6) sequence variation is previously not known or expected to be causative of disease, but is found to be associated with a clinical presentation. We emphasize the importance of appropriate reporting of sequence variations using standardized terminology and established databases, and of clearly reporting the limitations of sequence-based testing. We discuss follow-up studies that may be used to ascertain the clinical significance of sequence variations, including the use of additional tools (such as predictive software programs) that may be useful in variant classification. As more information becomes available allowing the interpretation of a new sequence variant, it is recommended that the laboratory amend previous reports and provide updated results to the physician. The ACMG strongly recommends that the clinical and technical validation of sequence variation detection be performed in a CLIA-approved laboratory and interpreted by a board-certified clinical molecular geneticist or equivalent. Genet Med 2008:10(4):294-300.These recommendations for the standardization of interpretation and reporting of sequence variations identified in the course of providing clinical laboratory services are intended (1) to provide a framework for laboratories for the interpretation and reporting of such test results, and (2) to aid referring clinicians by educating them as to possible testing outcomes so that they may inform their patients and families appropriately. These revised recommendations are based on the foundation laid by the previous ACMG practice guideline recommendations in 2000. 1 I. INTERPRETATIVE CATEGORIES AND DEFINITIONS OF SEQUENCE VARIATIONSIncreasingly, clinical molecular laboratories are detecting novel sequence variations in the course of testing patient spec-

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

“…A variant was considered pathogenic based on established criteria: (i) a missense variant with an amino acid change at a highly conserved position among species, (ii) a variant altering protein structure and function e.g., insertions and deletions causing a reading frameshift, and nonsense and splice-site mutations, (iii) previously reported as a cause of HCM, (iv) cosegregation with disease in the family, and (v) absence of the variant or in <1% among unrelated and ethnically matched controls. 5,7,15 VUS were those in which the effect on the protein function was not clear and disease-risk association with HCM was not known. Benign variants were considered synonymous variants that did not alter the amino acid sequence, and missense variants that were SNVs at a frequency of >1% in normal control populations.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Therefore, to harmonize the current evidence available for each gene we have applied general concepts of tumour predisposition genes 49 and the 'review status' established by ClinVar, the public archive of reports of the relationships among human variations and phenotypes curated by the National Center for Biotechnology Information (NCBI). ClinVar uses a five-level rank of evidence to establish variant pathogenicity that was suggested by the American College of Medical Genetics and Genomics 50,51 (TABLE 2). In this Consensus Statement, we adopted a modified version of ClinVar's 'gold star' scale to create three PPGLs panel types based on the current evidence of involvement of these genes in PPGLs susceptibility at the germ line (the basic premise for hereditary PPGLs screening) and somatic level.…”

Reporting Incidental Findings in Genomic Scale Clinical Sequencing—A Clinical Laboratory Perspective

“…Not all variants are pertinent to the patient's clinical presentation and, in fact, usually only one (for dominant disorders) or two variants (for recessive disorders) cause disease. 19 It is impossible to evaluate every single variant manually; therefore, bioinformatics analysis must be used to sort (filter) variants to narrow the number of relevant candidates. In the filtering process, the variants are assessed with several considerations, including population frequency of the variant, presence of the variant in clinical or sequencing databases such as Human Gene Mutation Database, ClinVar, Online Mendelian Inheritance in Man, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, and Locus-Specific Databases; likely mode of inheritance; phenotypic features and genes associated with these features; list of genes likely to explain the clinical presentation; predicted functional severity of the sequence change; variant type such as synonymous, missense, nonsense, frameshift, inframe; and pathogenic versus benign variants (ie, variants in internal databases that violate the Hardy Weinberg Equilibrium, variants present in unaffected homozygotes); tissue expression of a gene with a variant; relevance to the clinical phenotype of pathways in which the product of the variant gene participates, and so forth.…”

“…The interpretation of variant pathogenicity should follow the ACMG Recommendation for Interpretation of Sequence Variants. 19 The determination of pathogenicity for known variants is based on scientific literature, variant databases, and clinically validated/curated locus-specific databases, which support the assertion that the variants in question are causative of disease or not. For variant(s) that have not been reported previously, the known mechanism of disease and the ACMG guidelines should be followed.…”