NM_004333.6(BRAF):c.1799T>A (p.Val600Glu) AND Vascular malformation

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003458334.1

Allele description [Variation Report for NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)]

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

Gene:

BRAF:B-Raf proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

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

HGVS:

NC_000007.14:g.140753336A>T
NG_007873.3:g.176429T>A
NM_001354609.2:c.1799T>A
NM_001374244.1:c.1919T>A
NM_001374258.1:c.1919T>A
NM_001378467.1:c.1808T>A
NM_001378468.1:c.1799T>A
NM_001378469.1:c.1733T>A
NM_001378470.1:c.1697T>A
NM_001378471.1:c.1688T>A
NM_001378472.1:c.1643T>A
NM_001378473.1:c.1643T>A
NM_001378474.1:c.1799T>A
NM_001378475.1:c.1535T>A
NM_004333.6:c.1799T>AMANE SELECT
NP_001341538.1:p.Val600Glu
NP_001361173.1:p.Val640Glu
NP_001361187.1:p.Val640Glu
NP_001365396.1:p.Val603Glu
NP_001365397.1:p.Val600Glu
NP_001365398.1:p.Val578Glu
NP_001365399.1:p.Val566Glu
NP_001365400.1:p.Val563Glu
NP_001365401.1:p.Val548Glu
NP_001365402.1:p.Val548Glu
NP_001365403.1:p.Val600Glu
NP_001365404.1:p.Val512Glu
NP_004324.2:p.Val600Glu
NP_004324.2:p.Val600Glu
LRG_299t1:c.1799T>A
LRG_299:g.176429T>A
LRG_299p1:p.Val600Glu
NC_000007.12:g.140099605A>T
NC_000007.13:g.140453136A>T
NM_004333.4:c.1799T>A
NM_004333:c.1799T>A
P15056:p.Val600Glu
c.1799T>A
p.V600E

Protein change:

V512E; VAL600GLU

Links:

UniProtKB: P15056#VAR_018629; OMIM: 164757.0001; dbSNP: rs113488022

NCBI 1000 Genomes Browser:

rs113488022

Molecular consequence:

NM_001354609.2:c.1799T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1919T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1919T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1808T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1799T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1733T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1697T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1688T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1643T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1643T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1799T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1535T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1799T>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Increased function
gain_of_function_variant [Sequence Ontology: SO:0002053]

Condition(s)

Name:: Vascular malformation
Synonyms:: Vascular malformations
Identifiers:: MONDO: MONDO:0024291; MedGen: C0158570

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004176942	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 22, 2023)	somatic	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004176942

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 22, 2023)

somatic

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Clinical Genomics Laboratory, Washington University in St. Louis, SCV004176942.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	somatic	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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