Two In Cis Variants—Two Worlds Apart

Precision oncology emphasizes genotyping as one of the mainstays of oncological decision‐making. The core information element exchanged between the laboratory and the oncologist is the precise mutation. Specifically, it is the written representation typically in the form of a variant description at the DNA or protein level. These annotations can be confusing, and many commercial laboratories have abandoned DNA‐level annotations. Here we present a complex double‐point mutation to illustrate a situation where a formally “correct” reporting nomenclature can obscure clinically relevant and potentially clinically actionable information. Key Points The Human Genome Variation Society (HGVS) currently recommends that “two variants separated by one or more nucleotides should be described individually and not as a combined ‘delins’ (deletion‐inserion).” There remains confusion about the appropriate nomenclature to report variants and the significance of these variants among clinicians. It is the clinically integrated molecular‐genetic interpretation that will help clinicians make informed decisions to improve patient care. With the increasingly popular use of next‐generation sequencing for tumor genotyping, molecular pathologists encounter variants that are on the same allele and close enough to be combined and annotated together. This article reports a case of acute myeloid leukemia with two in cis IDH2 variants, illustrating the importance of correct variant annotation as good communication practices between molecular laboratories and oncologists.