BRAF NM_001354609.1:c.730A>C, Thr244Pro

Variant summary: BRAF c.730A>C (p.Thr244Pro) results in a non-conservative amino acid change located in the Protein kinase C-like, phorbol ester/diacylglycerol-binding domain (IPR002219) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249582 control chromosomes (gnomAD). c.730A>C has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome, Noonan syndrome and related conditions (Gripp_2007, Schulz_2008, Rodriguez-Viciana_2008, van Trier_2016, Leach_2018), including one de novo case. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters, including ClinGen RASopathy Variant Curation Expert Panel, (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine with proline at codon 244 of the BRAF protein (p.Thr244Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of the RASopathies spectrum. This variant occurred de novo in two of these affected individuals (PMID: 17551924, 27521173, 18042262). ClinVar contains an entry for this variant (Variation ID: 40346). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0").

The p.Thr244Pro variant in BRAF has been reported in the literature and our labo ratory in 6 individuals with RASopathies, three of which occurred de novo (Gripp 2007, Schulz 2008, LMM unpublished data). It was absent from large population s tudies. In summary, this variant meets our criteria to be classified as pathogen ic for RASopathies in an autosomal dominant manner (http://www.partners.org/pers onalizedmedicine/LMM) based upon de novo occurences and absence from controls.