There was sufficient genetic evidence in the literature for the association between BRAF and Noonan syndrome (NS) to be classified as Moderate. However, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NS versus cardiofaciocutaneous syndrome (CFC). Additional genotype-phenotype correlations are necessary to solidify the association of BRAF with Noonan syndrome (Lee et al., 2011; Nystrom et al., 2008; Razzaque et al., 2007; Sarkozy et al., 2009; van Trier et al., 2016). The BRAF gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype (Aoki, Niihori, Inoue, & Matsubara, 2016; Rauen, 2013). Of note, BRAF has also been classified as definitive in association with CFC, limited in association with NS with multiple lentigines, 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).
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