BRAF p.Phe247Val

The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3.