Classifying Germline Sequence Variants in the Era of Next-Generation Sequencing.

Abstract

Genetic medicine has taken tremendous strides in recent years due in large part to the clinical implementation of next-generation sequencing (NGS).10 Laboratories are now able to sequence more genes for less cost, resulting in advances in diagnostics, prognostics, therapeutic decision-making, and risk assessment. New germline and somatic gene/variant panel NGS tests are continually emerging, and exome/genome sequencing for rare inherited disorders is becoming more widely available. The increasing adoption of NGS testing has already led to a dramatic increase in the number of variants that need to be interpreted, ranging from completely novel variants to well-characterized variants with multiple publications describing their functional consequence. Catalyzed by the adoption of exome sequencing, an increasing need to evaluate the validity and strength of gene–disease association claims has emerged and adds yet another dimension to the already complex process of genomic data curation and interpretation. Depending on the amount of data available for a given variant (and its associated gene), clinical variant assessment can be a very challenging and time-consuming process. In addition, variants whose impact on the protein may be less obvious (e.g., missense variants) or variants in genes which are less well characterized may remain variants of uncertain clinical significance for quite some time, leading to an abundance of inconclusive results and possible confusion for ordering clinicians as well as patients. Clinical variant classification typically incorporates many data elements such as disease prevalence, variant frequency in patient and control populations, and gene function. However, these variables are often incomplete or poorly understood, further exacerbating the challenges for the overall medical community. Updated standards and guidelines for germline sequence variant interpretation were recently published as a joint consensus recommendation involving stakeholders from the American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology (AMP), and the College of …