The NF1 hotspot in acute myeloid leukemia: what’s in a name? (2024)

Subjects

• Acute myeloid leukaemia
• Cancer genetics
• Genetics research

Eisfeld and colleagues [1] recently described recurrent mutations in NF1 in patients with acute myeloid leukemia (AML), with a higher frequency than seen in previous studies. They show that mutations in hotspot Thr676 are associated with lower complete remission rates and shorter overall survival in patients <60 years. One of the factors that may have contributed to the previous oversight of this hotspot in previous studies, is its location in a mononucleotide cytosine repeat, which can easily be missed due to a faulty interpretation of sequencing data.

Changes in mononucleotide repeats are cumbersome in their technical analysis but also in their nomenclature. Initiatives by the Human Genome Variation Society (HGVS) are trying to limit the nomenclature variability by providing clear guidelines [2] how to describe such variants. The authors refer to the NF1 hotspot as “p.Thr676fs*24 [c.2026dupC], Thr676”. This annotation is in conflict with the HGVS guidelines in several ways: as the DNA sequence is determined, this should be prominent, and the derived amino acid sequence should be between brackets (as it is extrapolated from the change at the DNA level). Applying this rule, the annotation would change to “c.2026dupC; p.(Thr676fs*24)”. However, no reference sequence is provided, and nucleotide 2026 is not a C in the two reference sequences (NM_000267.3 and NM_001042492.2) used to determine the Locus Reference Genomic transcripts [3]. In both transcripts, the C-stretch runs from nucleotides 2027 to 2033. As stated in the HGVS guidelines [2], for duplications in stretches of repeated sequences, the most 3′ residue is arbitrarily assigned to have been changed, resulting in a reassignment of the NF1 hotspot to c.2033 in the DNA sequence and from Thr676 to Ile679 in the protein. In conclusion, the HGVS compliant nomenclature of an additional cytosine in this C-stretch is NM_001042492.2:c.2033dup; p.(Ile679Aspfs*21). The Ile679 amino acid annotation is also used in the AACR GENIE dataset, to which the authors refer to confirm their results. The recognition of Ile679 as a hotspot for NF1 mutations, if confirmed in other studies, would benefit significantly from the use of a uniform nomenclature, following the HGVS guidelines.

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