What should be considered when evaluating genetic variants?
The mutation type of the variants (eg, nonsense versus missense or frameshift versus in-frame deletion or duplication) and the main function of the gene (eg, tumor suppressors versus oncogenes) should be considered when evaluating this group of variants.
How should we interpret somatic variants?
Unlike interpretation of germline sequence variations, which focuses on pathogenicity of a variant for a specific disease or disease causality, interpretation of somatic variants should be focused on their impact on clinical care.
What are called variants and why are they important?
Certain metrics for called variants are critical for variant interpretation, such as supporting reads (depth of coverage) and variant allele frequency (VAF), and should be included in variant evaluation; the latter is particularly important for somatic variant interpretation in the absence of paired normal and for evaluating tumor clonal diversity.
What germline variants should I report?
We recommend reporting germline variants with known evidence of clinical impact. An example of germline variants with therapeutic impact is pathogenic germline variants of BRCA1/2.
What is sequence variant classification?
The guidelines for the interpretation of sequence variants formulated through the joint efforts of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) are an important framework to standardize how laboratories, researchers, clinicians, and others categorize and curate the ever-increasing number of sequence variants uncovered during the course of molecular testing to determine the genetic etiology of human diseases . 1 Accurate variant classifications are critical for clinical management decisions and recurrence risk discussions, in addition to guiding research pursuits and determining eligibility for clinical trials. Assigning a pathogenic or benign direction and strength to a variant relies on information in population, disease-specific, and sequence databases; predictions from numerous in silico algorithms; inheritance patterns; and the published literature. If there is an insufficient amount of relevant data, then a classification of “uncertain significance” is assigned. Functional studies can assist in these circumstances and thus comprise strong criteria in determining a variant’s pathogenic (PS3) or benign (BS3) nature. However, model or experimental systems have inherent limitations, it is difficult to test every identified variant, and often, functional assays do not exist or are not readily accessible.
What is extended evaluation?
Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families.
