rs397507483
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001374258.1(BRAF):c.1907G>T(p.Gly636Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G636C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001374258.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.1907G>T | p.Gly636Val | missense_variant | 16/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.1787G>T | p.Gly596Val | missense_variant | 15/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1907G>T | p.Gly636Val | missense_variant | 16/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.1787G>T | p.Gly596Val | missense_variant | 15/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RASopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 01, 2022 | 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). - |
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | 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. - |
Cardiofaciocutaneous syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 20, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PM2,PM6_Strong,PP2,PP3,PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 18, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2013 | 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). - |
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - CFC International | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 10, 2014 | 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/). - |
Glioblastoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2018 | - - |
Multiple myeloma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lung adenocarcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Cardio-facio-cutaneous syndrome Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at