Given the extent to which we observed NF1 loss-of-function variants in normal tissues, it seems reasonable to propose that although in certain contexts second hits may be sufficient to cause neoplasia10,11, as suggested by our case’s café au lait spot and spindle cell lesion, transformation to a discernible tumor is an uncommon immediate outcome of biallelic NF1 loss. This evidence concerns the gene NF1 and neoplasm.