RT Journal Article SR Electronic T1 Breast cancer risk in neurofibromatosis type 1 is a function of the type of NF1 gene mutation: a new genotype-phenotype correlation JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 209 OP 219 DO 10.1136/jmedgenet-2018-105599 VO 56 IS 4 A1 Ian M Frayling A1 Victor-Felix Mautner A1 Rick van Minkelen A1 Roope A Kallionpaa A1 Safiye Aktaş A1 Diana Baralle A1 Shay Ben-Shachar A1 Alison Callaway A1 Harriet Cox A1 Diana M Eccles A1 Salah Ferkal A1 Holly LaDuca A1 Conxi Lázaro A1 Mark T Rogers A1 Aaron J Stuenkel A1 Pia Summerour A1 Ali Varan A1 Yoon Sim Yap A1 Ouidad Zehou A1 Juha Peltonen A1 D Gareth Evans A1 Pierre Wolkenstein A1 Meena Upadhyaya YR 2019 UL http://jmg.bmj.com/content/56/4/209.abstract AB Background Neurofibromatosis type 1 (NF1) predisposes to breast cancer (BC), but no genotype-phenotype correlations have been described.Methods Constitutional NF1 mutations in 78 patients with NF1 with BC (NF1-BC) were compared with the NF1 Leiden Open Variation Database (n=3432).Results No cases were observed with whole or partial gene deletions (HR 0.10; 95% CI 0.006 to 1.63; p=0.014, Fisher’s exact test). There were no gross relationships with mutation position. Forty-five (64.3%; HR 6.4–83) of the 70 different mutations were more frequent than expected (p<0.05), while 52 (74.3%; HR 5.3–83) were significant when adjusted for multiple comparisons (adjusted p≤0.125; Benjamini-Hochberg). Higher proportions of both nonsense and missense mutations were also observed (adjusted p=0.254; Benjamini-Hochberg). Ten of the 11 missense cases with known age of BC occurred at <50 years (p=0.041). Eighteen cases had BRCA1/2 testing, revealing one BRCA2 mutation.Discussion These data strongly support the hypothesis that certain constitutional mutation types, and indeed certain specific variants in NF1 confer different risks of BC. The lack of large deletions and excess of nonsenses and missenses is consistent with gain of function mutations conferring risk of BC, and also that neurofibromin may function as a dimer. The observation that somatic NF1 amplification can occur independently of ERBB2 amplification in sporadic BC supports this concept. A prospective clinical-molecular study of NF1-BC needs to be established to confirm and build on these findings, but regardless of NF1 mutation status patients with NF1-BC warrant testing of other BC-predisposing genes.