Submissions for variant NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)

dbSNP: rs113488022

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080903	SCV000112810	pathogenic	not provided	2013-10-08	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000080903	SCV001450230	pathogenic	not provided	2014-07-11	criteria provided, single submitter	clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458334	SCV004176942	pathogenic	Vascular malformation	2023-10-22	criteria provided, single submitter	clinical testing	The BRAF c.1799T>A (p.Val600Glu) variant was identified at an allelic fraction consistent with somatic origin. This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs in a highly conserved residue within the CR3 activation segment, amino acids 594-627, of BRAF that is defined as a critical functional domain (Wellbrock C, et al., PMID: 15520807; Gelb BD, et al., PMID: 29493581). The BRAF c.1799T>A (p.Val600Glu) variant in a somatic state has been reported in multiple individuals affected with sporadic vascular malformations, brain arteriovenous malformation (BAVM) and spinal arteriovenous malformation (SAVM) (Hong T, et al., PMID: 30544177; Al-Olabi L, et al., PMID: 29461977; Goss JA, et al., PMID: 31891627; Li H, et al., PMID: 34530633). The BRAF c.1799T>A (p.Val600Glu) variant has been reported in the ClinVar database as pathogenic by numerous submitters (ClinVar ID: 13961). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies show constitutively active kinase activity (Rodriguez-Viciana P, et al., PMID: 16439621; Sarkozy A, et al., PMID:19206169; Al-Olabi L, et al., PMID: 29461977). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as pathogenic.
Ambry Genetics	RCV004018627	SCV005022010	likely pathogenic	Cardiovascular phenotype	2022-05-23	criteria provided, single submitter	clinical testing	ASSESSED FOR SOMATIC SAMPLE ONLY. FOR ANY GERMLINE INDICATION, PLEASE REASSESS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089260	SCV005812663	uncertain significance	RASopathy	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 600 of the BRAF protein (p.Val600Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported as a known somatic variant in various cancers but has not been reported in the literature in individuals affected with germline BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13961). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. This variant disrupts the p.Val600 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000067669	SCV000035247	pathogenic	Melanoma	2014-09-04	no assertion criteria provided	literature only
OMIM	RCV000014992	SCV000035248	pathogenic	Carcinoma of colon	2014-09-04	no assertion criteria provided	literature only
OMIM	RCV000014993	SCV000035249	pathogenic	Papillary thyroid carcinoma	2014-09-04	no assertion criteria provided	literature only
OMIM	RCV000014994	SCV000035250	pathogenic	Astrocytoma, low-grade, somatic	2014-09-04	no assertion criteria provided	literature only
OMIM	RCV000022677	SCV000043966	pathogenic	Nongerminomatous germ cell tumor	2014-09-04	no assertion criteria provided	literature only
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037936	SCV000061601	pathogenic	Non-small cell lung carcinoma	2009-05-29	no assertion criteria provided	clinical testing
GeneReviews	RCV000208763	SCV000264636	not provided	Cardio-facio-cutaneous syndrome		no assertion provided	literature only
Yale Center for Mendelian Genomics, Yale University	RCV000662278	SCV000784606	pathogenic	Cystic epithelial invagination containing papillae lined by columnar epithelium	2015-05-07	no assertion criteria provided	literature only
Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	RCV000860020	SCV000992587	pathogenic	Cerebral arteriovenous malformation		no assertion criteria provided	research
Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center	RCV000430562	SCV001132084	likely pathogenic	Multiple myeloma	2019-08-31	no assertion criteria provided	clinical testing
Pediatric Oncology, Johns Hopkins University	RCV001248834	SCV001147031	pathogenic	Nephroblastoma	2019-02-15	no assertion criteria provided	clinical testing
Investigational Cancer Therapeutics, MD Anderson Cancer Center	RCV001254874	SCV001424772	likely pathogenic	Malignant neoplastic disease		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000080903	SCV001550994	uncertain significance	not provided		no assertion criteria provided	clinical testing
Sylvester Comprehensive Cancer Center, University of Miami	RCV000080903	SCV001962698	pathogenic	not provided		no assertion criteria provided	clinical testing	BRAF V600E variant is involved in encoding cytoplasmic serine/threonine kinases within the MAPK pathway. The NCCN Guidelines state that BRAF mutations are an indicative prognostic marker with poor clinical outcome. It it recommended to do baseline genomic genotyping of the patient's primary or metastatic tumor tissue at diagnosis if the patient is stage IV. BRAF V600E is mutated in about 15% of all cancers (El-Osta et. al, 2011). Frequency of all RAF mutations is 2.2% within pancreatic cancer, where BRAF V600E is one of the more common variants, and is actionable (Hendifar et al., 2021)
Yale Center for Mendelian Genomics, Yale University	RCV000662278	SCV002106413	pathogenic	Cystic epithelial invagination containing papillae lined by columnar epithelium	2015-05-07	no assertion criteria provided	literature only
James Bennett Lab, Seattle Childrens Research Institute	RCV002051586	SCV002318371	pathogenic	Lymphangioma	2022-02-09	no assertion criteria provided	research	The Val600Glu variant in BRAF was observed at very low levels (VAF 0.3-2%) in lymphatic malformation tissue from three unrelated individuals using high depth NGS (VANseq), confirmatory digital droplet PCR, and BRAF V600E immunohistochemistry.