The c.1796C>T (p.Thr599Ille) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been reported as a de novo occurrence with parentage confirmed in 1 proband diagnosed with cardiofaciocutaneous syndrome (PS2, PS4_Supporting; PMID 30732632). This variant was also observed as a de novo occurrence without parentage confirmed in proband with phenotypic features of a RASopathy but no clinical diagnosis (PM6; GeneDx internal data, SCV000057239.11). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr599Ile variant may impact the protein (PP3). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.