President's Corner - Quantitative Interpretation of Sequence Variants
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Interpretation of sequence variants is certainly one of the greatest current challenges in clinical genetics. Despite the impressive new ACMG interpretation guidelines (Richards et al. 2015 Genet Med 17:405-424), variant interpretation is still a highly subjective exercise. Two highly experienced and skilled geneticists each examining exactly the same evidence will often come up with different interpretations. In an effort to make interpretation more objective, we have been working at PreventionGenetics to develop several simple, quantitative measures of pathogenicity. Our results have been presented at the ACMG and ICHG meetings earlier this year, and will be presented at the ASHG meeting in Vancouver this fall. In this article, I provide rationale and introduction to our approaches. In the second part of this series, I will provide a more detailed description of the two quantitative approaches we have developed along with some of the supporting evidence.
At least in North America, and perhaps gradually throughout the world, sequence variants (defined as differences between patient sequences and reference sequences) are now classified into five groups: Pathogenic, Likely Pathogenic, Uncertain, Likely Benign and Benign. Objective interpretation must begin with quantitative definitions of these group labels. Much more discussion needs to take place before even national consensus about quantitative definitions is reached, but the values currently used at PreventionGenetics are shown in the accompanying Table. These values are the probabilities that the interpretation assignments are incorrect; for example a variant that is classified as Likely Pathogenic should have no more than a 5% chance of being benign. Note that our definitions are conservative. We want only a small chance that our assignments of “pathogenic” or “benign” are incorrect. When there is more than a small chance, we classify the variants as Uncertain.
Our two quantitative approaches involve allele frequency differences between cases and controls, and the fraction of times a particular variant occurs together with a second plausible pathogenic variant in patients affected with recessive disorders. These approaches have limitations as well as potential pitfalls and therefore must be used with caution. The results of the quantitative approaches should also always be considered together with all available qualitative evidence. Nevertheless, these approaches are important first steps in transforming sequence interpretation from an art to a science. We are cautiously, but steadily applying these quantitative approaches to variant interpretation at PreventionGenetics.
-James L. Weber, PhD
Founder & President, PreventionGenetics