NM_004333.6(BRAF):c.1914T>A (p.Asp638Glu) AND Cardiofaciocutaneous syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Apr 7, 2025
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:: RCV000015015.37

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

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

HGVS:

NC_000007.14:g.140749365A>T
NG_007873.3:g.180400T>A
NM_001354609.2:c.1914T>A
NM_001374244.1:c.2034T>A
NM_001374258.1:c.2034T>A
NM_001378467.1:c.1923T>A
NM_001378468.1:c.1914T>A
NM_001378469.1:c.1848T>A
NM_001378470.1:c.1812T>A
NM_001378471.1:c.1803T>A
NM_001378472.1:c.1758T>A
NM_001378473.1:c.1758T>A
NM_001378474.1:c.1914T>A
NM_001378475.1:c.1650T>A
NM_004333.6:c.1914T>AMANE 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>A
LRG_299:g.180400T>A
NC_000007.13:g.140449165A>T
NM_004333.4:c.1914T>A
P15056:p.Asp638Glu

Protein change:

D550E; ASP638GLU

Links:

UniProtKB: P15056#VAR_058630; OMIM: 164757.0021; dbSNP: rs180177042

NCBI 1000 Genomes Browser:

rs180177042

Molecular consequence:

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

Observations:

Condition(s)

Name:: Cardiofaciocutaneous syndrome 1 (CFC1)
Identifiers:: MONDO: MONDO:0007265; MedGen: CN029449; Orphanet: 1340; OMIM: 115150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035271	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2006)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16372351, 16804887
SCV000680155	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Sep 8, 2017)	de novo	clinical testing	Citation Link,
SCV000781088	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000965743	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001528180	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2018)	de novo	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16804887, 19206169, 25741868
SCV003925531	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 16, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005903492	Department of Human Genetics, Hannover Medical School	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 7, 2025)	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	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.

Estep AL, Tidyman WE, Teitell MA, Cotter PD, Rauen KA.

Am J Med Genet A. 2006 Jan 1;140(1):8-16.

PubMed [citation]

PMID:: 16372351

Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype.

Rauen KA.

Am J Med Genet A. 2006 Aug 1;140(15):1681-3. No abstract available.

PubMed [citation]

PMID:: 16804887

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000035271.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a 13-year-old girl with phenotypic features overlapping cardiofaciocutaneous (CFC1; 115150) and Costello (218040) syndromes, in whom no HRAS (190020) mutation was found (Estep et al., 2006), Rauen (2006) identified a 1914T-A transversion in exon 16 of the BRAF gene, resulting in an asp638-to-glu (D638E) substitution, and noted that CFC-causing BRAF mutations had not previously been described in exon 16.

#	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		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680155.2

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

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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781088.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV000965743.1

#	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001528180.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing in a patient with features overlapping cardiofaciocutaneous and Costello syndromes [PMID 16804887] In addition, a different variant at this nucleotide position (c.1914T>G) resulting in the same amino acid residue change has been previously reported as disease causing in patients with cardiofaciocutaneous syndrome [PMID 19206169]

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

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003925531.2

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

Description

A heterozygous missense variation in exon 16 of the BRAF gene that results in the amino acid substitution of glutamic acid for aspartic acid at codon 638 was detected. The observed variant c.1914T>A (p.Asp638Glu) variant has not been observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by FATHMM, LRT, Mutation Assessor, Mutation Taster and SIFT. In summary, the variant meets our criteria to be classified as a likely pathogenic.

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

From Department of Human Genetics, Hannover Medical School, SCV005903492.1

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

Description

ClinGen VCEP: (PS1, PS4_Supporting, PM2_Supporting, PM6_Strong, PP2, PP3

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

Last Updated: May 16, 2025

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