• Genetic Counseling
• Genetic Predisposition to Disease
• Genetics, Medical
• Human Genetics
• Medical Oncology

Neurofibromatosis type 1 (NF1, OMIM #162200) is a genetic condition with an autosomal dominant transmission. The disorder is caused by loss-of-function variants in NF1. The tumour suppressor gene NF1 (OMIM *613113) encodes neurofibromin, a negative regulator of the RAS-mitogen-activated protein kinase (MAPK) pathway. NF1 is associated with an increased risk of developing malignant tumours, mainly malignant peripheral nerve sheath tumours.1

NF1 women were previously reported to have standardised incidence ratio (SIR) for the development of breast cancer (BC) of 3.5 compared with the general population,2 with an SIR of 11.1 in women aged under 40 years.3 Some NF1 patients were eventually described with bilateral BC,4–8 a poor prognosis condition.9 In a study published in 2019, Frayling et al identified the germline NF1 pathogenic variants in an international cohort of 78 NF1 patients with BC.10 They observed a high prevalence of nonsense and missense NF1 pathogenic variants in this group, and a complete absence of whole NF1 locus deletion.11 Type-1 deletions are the most frequent recurrent NF1 deletions resulting from non-allelic homologous recombination between low copy repeats at the NF1 locus. The resulting deletions measure 1.4 Mb and comprise 13 coding genes in addition to NF1. This observation by Frayling et al seemed inconsistent with the more severe phenotype previously described in NF1-deletion patients, including an increased tumour risk versus NF1 patients with NF1 point pathogenic variants.12 13 Frayling et al suggested that the overall low prevalence of BC in NF1-deletion patients subgroup (1) might be related to their reduced life expectancy with a subsequent reduced likelihood to develop late-onset complications or (2) that BC might be favoured by specific gain-of-function variants rather than loss-of-function variants in …