Submissions for variant NM_001374258.1(BRAF):c.1907G>T (p.Gly636Val) (rs397507483)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000033332	SCV000616388	pathogenic	Rasopathy	2017-04-03	reviewed by expert panel	curation	The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.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). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PP2, PP3, PM1.
GeneDx	RCV000077865	SCV000057237	pathogenic	not provided	2013-05-22	criteria provided, single submitter	clinical testing	p.Gly596Val (GGT>GTT): c.1787 G>T in exon 15 of the BRAF gene (NM_004333.4). The G596V mutation in the BRAF gene has been previously reported in at least 4 unrelated patients with Cardio-Facio-Cutaneous syndrome (Rodriguez-Viciana et al., 2006). This mutation falls within the activation loop located within the third conserved region of the BRAF protein. The G596V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000077865	SCV000058306	pathogenic	not provided	2013-03-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000844615	SCV000197137	pathogenic	Noonan syndrome; Cardio-facio-cutaneous syndrome	2014-09-10	criteria provided, single submitter	clinical testing	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/).
Invitae	RCV000033332	SCV000936651	pathogenic	Rasopathy	2018-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with valine at codon 596 of the BRAF protein (p.Gly596Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with cardio-facio-cutaneous syndrome, in some of whom it was found de novo (PMID: 16439621, 25463315). ClinVar contains an entry for this variant (Variation ID: 40387). Experimental studies have shown that this missense change causes a decrease in phosphorylation and kinase activity of downstream enzymes, as well as developmental changes in zebrafish embryos (PMID: 16439621, 18413255, 19376813); however, the clinical significance of these findings is unclear. For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856749	SCV000999297	pathogenic	Cardiofaciocutaneous syndrome 1		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001198417	SCV001369351	pathogenic	Epicanthus; Telecanthus; Abnormal facial shape; Ventriculomegaly; Curly hair; Severe global developmental delay; Thick vermilion border; Wide nasal base	2019-08-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in heterozygous state.
Baylor Genetics	RCV000033332	SCV000196671	pathogenic	Rasopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
GeneReviews	RCV000208758	SCV000264635	pathogenic	Cardio-facio-cutaneous syndrome	2016-03-03	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438697	SCV000505826	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424067	SCV000505827	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431311	SCV000505828	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441123	SCV000505829	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
GenomeConnect - CFC International	RCV000844615	SCV001156342	not provided	Noonan syndrome; Cardio-facio-cutaneous syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-03-2010 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.