In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) published guidelines establishing a classification system for sequence variant interpretation [1]. These guidelines were quickly adopted, as they allowed the uniformization of variant annotation in clinical reports and research studies [2]. They were designed to be broadly applicable to thousands of disease genes and clinical scenarios, and they have affected how most clinical genetics professionals present variant information to families. However, the classification presents shortcomings, for example in classifying variants of moderate to low penetrance, classifying recessive variants, or variants in genes contemporaneously associated with diseases. It was also not designed to classify copy number variants (CNVs). The Variant of Unknown Significance (VUS) category is broad and captures many ultra-rare variants, for example when there are too few elements to suggest pathogenicity or when there are conflicting pathogenicity clues. When reports are read by non-experts, the subtleties as to why a variant is classified as a VUS are often not well understood, and the result can be interpreted to be normal, or to confirm a diagnosis, when it may not be the case. The guidelines do allow for laboratories to add extra tiers or subcategories to the classification, and these are especially useful when variants are classified as VUSs. However, these additional subcategories are generally not accepted when submitting data to ClinVar.

Several modifications or additions to the classification system have been proposed, such as the Sherloc classification scheme from the company Invitae [3], or efforts of the NIH-funded Clinical Genome Resource (ClinGen) such as the CNV Interpretation Calculator, a Bayesian calculation framework, and gene- or gene group-specific Variant Curation Expert Panels [4,5,6]. In 2019, an ad hoc working group of the European Society of Human Genetics (ESHG) proposed a two-dimensional system for variant classification. The goal of such a system was to address some of the limitations of the ACMG-AMP classification system for certain variant types or genes, and to be more broadly applicable without requiring gene-specific classification systems, for example. This effort has evolved into the stepwise ABC classification system, which takes into consideration functional and clinical available data, and allows for an optional comment to reflect, for example, local policy [7]. This classification can be used as an alternative to the ACMG-AMP classification or an addition to it (i.e. as an optional tier), and is not ESHG Board-endorsed. Its use by a broad array of laboratories, and the description of the ABC classification and grades in the comments section of ClinVar submissions, for example, could allow for a wide assessment of its clinical utility, which is already clear to many.