Submissions for variant NM_004333.6(BRAF):c.1502A>T (p.Glu501Val)

dbSNP: rs180177039

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033318	SCV000057223	pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 18039235, 30094826, 33040082, 17704260)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037924	SCV000061588	likely pathogenic	Cardio-facio-cutaneous syndrome	2014-09-24	criteria provided, single submitter	clinical testing	The Glu501Val variant in BRAF has been reported in three individuals with clinic al features of Cardio-facio-cutaneous syndrome (Yoon 2007, Nava 2007, LMM unpubl ished data). It was also absent from large population studies. Different disease -causing amino acid changes (Glu501Lys, Glu501Gly) at this location have been id entified in >10 affected individuals and both of these variants were reported to have occurred de novo in two individuals (Razzaque 2007,Narumi 2007, Niihori 20 06, Rodriguez-Viciana 2006,Rodriguez-Viciana 2008, LMM unpublished data) suggest ing that changes at this position are not tolerated. Additionally, computational prediction tools and evolutionary conservation analysis suggest that the Glu501 Val variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the Glu501Val variant is likely pa thogenic, though additional studies are required to fully establish its clinical significance.
3billion, Medical Genetics	RCV001775071	SCV002011970	pathogenic	Cardiofaciocutaneous syndrome 1	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (VCV000040374.2, PMID: 17704260, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Glu501Lys, p.Glu501Gly, p.Glu501Ala) at the same codon has been reported as pathogenic (ClinVar ID: VCV000013977.4, VCV000013978.7, VCV000040373.5, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.995, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852671	SCV002233097	pathogenic	RASopathy	2021-07-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu501 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 40374). This variant has been observed in individuals with cardiofaciocutaneous syndrome (PMID: 18039235, 30094826). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with valine at codon 501 of the BRAF protein (p.Glu501Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV001775071	SCV003840147	pathogenic	Cardiofaciocutaneous syndrome 1		no assertion criteria provided	research