Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2_SupportingPM5PP2PP3_ModeratePP5_Very_Strong
The NM_001374258(BRAF):c.1919T>G(p.Val640Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic 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. V640A) has been classified as Likely pathogenic.
Verdict is Pathogenic. Variant got 16 ACMG points.
GnomAD3 genomesCov.: 32
Submissions by phenotype
|Pathogenic, reviewed by expert panel||curation||ClinGen RASopathy Variant Curation Expert Panel||Jun 25, 2020||The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). 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). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the variant is located in BRAF, 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). 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): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. -|
|Pathogenic, criteria provided, single submitter||clinical testing||Invitae||Aug 30, 2022||This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 600 of the BRAF protein (p.Val600Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 20735442). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40389). 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. For these reasons, this variant has been classified as Pathogenic. -|
|Pathogenic, no assertion criteria provided||literature only||Database of Curated Mutations (DoCM)||Oct 02, 2014||- -|
|Uncertain significance, no assertion criteria provided||clinical testing||Department of Pathology and Laboratory Medicine, Sinai Health System||-||- -|
|not provided, no assertion provided||literature only||GeneReviews||-||- -|
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