NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu) AND Cardio-facio-cutaneous syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 14, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000150199.7

Allele description [Variation Report for NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)]

NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)

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.1914T>G (p.Asp638Glu)

Other names:

p.D638E:GAT>GAG

HGVS:

NC_000007.14:g.140749365A>C
NG_007873.3:g.180400T>G
NM_001354609.2:c.1914T>G
NM_001374244.1:c.2034T>G
NM_001374258.1:c.2034T>G
NM_001378467.1:c.1923T>G
NM_001378468.1:c.1914T>G
NM_001378469.1:c.1848T>G
NM_001378470.1:c.1812T>G
NM_001378471.1:c.1803T>G
NM_001378472.1:c.1758T>G
NM_001378473.1:c.1758T>G
NM_001378474.1:c.1914T>G
NM_001378475.1:c.1650T>G
NM_004333.6:c.1914T>GMANE SELECT
NP_001341538.1:p.Asp638Glu
NP_001361173.1:p.Asp678Glu
NP_001361187.1:p.Asp678Glu
NP_001365396.1:p.Asp641Glu
NP_001365397.1:p.Asp638Glu
NP_001365398.1:p.Asp616Glu
NP_001365399.1:p.Asp604Glu
NP_001365400.1:p.Asp601Glu
NP_001365401.1:p.Asp586Glu
NP_001365402.1:p.Asp586Glu
NP_001365403.1:p.Asp638Glu
NP_001365404.1:p.Asp550Glu
NP_004324.2:p.Asp638Glu
LRG_299t1:c.1914T>G
LRG_299:g.180400T>G
NC_000007.13:g.140449165A>C
NM_004333.4:c.1914T>G
NM_004333.5:c.1914T>G
NM_004333.6:c.1914T>G
P15056:p.Asp638Glu

Protein change:

D550E

Links:

UniProtKB: P15056#VAR_058630; dbSNP: rs180177042

NCBI 1000 Genomes Browser:

rs180177042

Molecular consequence:

NM_001354609.2:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.2034T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.2034T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1923T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1848T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1812T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1803T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1758T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1758T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1650T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1914T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardio-facio-cutaneous syndrome
Synonyms:: Cardiofaciocutaneous syndrome; CFC syndrome
Identifiers:: MONDO: MONDO:0015280; MedGen: C1275081; Orphanet: 1340; OMIM: PS115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000197128	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Aug 27, 2013)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18413255, 19206169, 21063443, 16804887, 24033266
SCV005016614	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	germline	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

SCV000197128

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Aug 27, 2013)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV005016614

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 14, 2024)

germline

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	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.

Rodriguez-Viciana P, Rauen KA.

Methods Enzymol. 2008;438:277-89. doi: 10.1016/S0076-6879(07)38019-1.

PubMed [citation]

PMID:: 18413255

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, et al.

Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955.

PubMed [citation]

PMID:: 19206169
PMCID:: PMC4028130

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000197128.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence.

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV005016614.1

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

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

Last Updated: Nov 18, 2024

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