Submission Details

There was only sufficient evidence in the literature for the association between BRAF and Noonan syndrome with multiple lentigines (NSML) to be classified as Limited. Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NSML versus other BRAF-RASopathies. Additional genotype-phenotype correlations are necessary to solidify the association of BRAF with NSML. Of note, variants identified in patients with cardiofaciocutaneous syndrome (CFC) diagnoses have also been identified in patients with NS, thus complicating the possibility of a genotype-phenotype correlation (Carcavilla et al., 2013; Ezquieta et al., 2012; Koudova, Seemanova, & Zenker, 2009; Sarkozy et al., 2009). The BRAF gene is also located in the Ras/MAPK pathway which is directly associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). Additionally, BRAF has been classified as definitive in association with CFC syndrome, moderate in association with NS, and disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating BRAF with NS with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).