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Acute myeloid leukemia

Implementation of standardized variant-calling nomenclature in the age of next-generation sequencing: where do we stand?

Leukemia volume 33, pages 809–810 (2019)Cite this article

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We appreciate the comments of Vandepoele et al [1]. concerning our recent study on NF1 mutations in acute myeloid leukemia [2], which raise important points warranting discussion. We agree that using standardized guidelines for nomenclature of genetic variants, such as those of the Human Genome Variation Society (HGVS) [3], is an important way to streamline and hone communication between researchers and to prevent using duplicate names for identical variants due to varying interpretation of variant locations. Following HGVS guidelines, the NF1 mutation hotspot highlighted in our article [2], which we referred to as “p.Thr676fs*24 [c.2026dupC], Thr676” would be changed to “c.2033dup; p.(Ile679Aspfs*21)”, based on the reference sequence of NM_001042492.2. We would like to thank Vandepoele et al. [1] for their comments, as indeed the identical variant referenced in our manuscript has been differently named in various publications and databases. For example, when described in juvenile myelomonocytic leukemia this variant was named “p.Thr676” and “c.2026insC” [4], whereas it was called “NF1:NM_000267:exon18:c.2410_dupC:p.T676fs” when described in a patient with refractory anemia with excess of blasts in transformation [5]. In fact, the COSMIC database (https://cancer.sanger.ac.uk/cosmic/) currently lists this mutation as three different entries (c.2026_2027insC, c.2027_2028insC, and c.2032_2033insC), while the AACR GENIE database (cbioportal.org/genie/) shows a single “I679Dfs*21; FS ins” mutation.

However, despite the additional clarity provided by the use of HGVS notation, ambiguity can remain. For example, minor allele assignments change between genome builds, exons are added and removed, and alternative start codons can shift coding sequence numbering. The Locus Reference Genomic (LRG; https://www.lrg-sequence.org/) project was created to combat these types of issues [6], and is now recommended by HGVS as the preferred reference sequence identifier for coding variants. Accordingly, our variant would be identified as belonging to LRG_214t2.

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Author notes

  1. These authors contributed equally: Ann-Kathrin Eisfeld, James S. Blachly.

Authors and Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Ann-Kathrin Eisfeld, James S. Blachly, Krzysztof Mrózek, Jessica Kohlschmidt, Christopher J. Walker, Albert de la Chapelle & Clara D. Bloomfield

  2. Alliance for Clinical Trials in Oncology Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    Jessica Kohlschmidt

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  1. Ann-Kathrin Eisfeld
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Correspondence to Ann-Kathrin Eisfeld, Krzysztof Mrózek or Clara D. Bloomfield.

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Eisfeld, AK., Blachly, J.S., Mrózek, K. et al. Implementation of standardized variant-calling nomenclature in the age of next-generation sequencing: where do we stand?. Leukemia 33, 809–810 (2019). https://doi.org/10.1038/s41375-018-0372-x

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