BRAF NM_001354609.1:c.1787G>T, Gly596Val

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRAF function (PMID: 16439621, 18413255, 19376813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40387). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 25463315). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 596 of the BRAF protein (p.Gly596Val).

Variant classified using ACMG guidelines

The Gly596Val variant has been identified in 7 individuals with clinical feature s of Cardio-facio-cutaneous syndrome (CFC) and 3 individuals with clinical featu res of Noonan syndrome (Rodriguez-Viciana 2006, Yoon 2007, Rodriguez-Viciana 200 8, LMM unpublished data). It was absent from large population studies. In-vitro functional studies provide some evidence that the Gly596Val variant may impact p rotein function (Rodrigues-Viciana 2006). Furthermore, animal models in zebrafis h have shown that this variant causes severe developmental abnormalities (Anasta saki 2009). In summary, this variant meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/).