NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 8, 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:: RCV000808147.7

Allele description [Variation Report for NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly)]

NM_004333.6(BRAF):c.1502A>G (p.Glu501Gly)

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.1502A>G (p.Glu501Gly)

Other names:

p.E501G:GAA>GGA

HGVS:

NC_000007.14:g.140778006T>C
NG_007873.3:g.151759A>G
NM_001354609.2:c.1502A>G
NM_001374244.1:c.1622A>G
NM_001374258.1:c.1622A>G
NM_001378467.1:c.1511A>G
NM_001378468.1:c.1502A>G
NM_001378469.1:c.1436A>G
NM_001378470.1:c.1400A>G
NM_001378471.1:c.1391A>G
NM_001378472.1:c.1346A>G
NM_001378473.1:c.1346A>G
NM_001378474.1:c.1502A>G
NM_001378475.1:c.1238A>G
NM_004333.6:c.1502A>GMANE SELECT
NP_001341538.1:p.Glu501Gly
NP_001361173.1:p.Glu541Gly
NP_001361187.1:p.Glu541Gly
NP_001365396.1:p.Glu504Gly
NP_001365397.1:p.Glu501Gly
NP_001365398.1:p.Glu479Gly
NP_001365399.1:p.Glu467Gly
NP_001365400.1:p.Glu464Gly
NP_001365401.1:p.Glu449Gly
NP_001365402.1:p.Glu449Gly
NP_001365403.1:p.Glu501Gly
NP_001365404.1:p.Glu413Gly
NP_004324.2:p.Glu501Gly
LRG_299t1:c.1502A>G
LRG_299:g.151759A>G
NC_000007.13:g.140477806T>C
NM_004333.4:c.1502A>G
P15056:p.Glu501Gly
c.1502A>G

Protein change:

E413G; GLU501GLY

Links:

UniProtKB: P15056#VAR_026117; OMIM: 164757.0018; dbSNP: rs180177039

NCBI 1000 Genomes Browser:

rs180177039

Molecular consequence:

NM_001354609.2:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1622A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1622A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1511A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1436A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1400A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1391A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1346A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1346A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1238A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1502A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

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CPXV050 protein [Cowpox virus]
CPXV050 protein [Cowpox virus]
gi|554572026|gb|AGY97709.1|

Protein
kelch-like protein [Cowpox virus]
kelch-like protein [Cowpox virus]
gi|325559283|gb|ADZ30658.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000948240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19206169, 20186801, 25463315, 16439621, 16474404, 17483702, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000948240

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 8, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome.

Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Rauen KA, Seidenberg MS.

Am J Med Genet A. 2010 Mar;152A(3):591-600. doi: 10.1002/ajmg.a.33268.

PubMed [citation]

PMID:: 20186801
PMCID:: PMC3085983

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948240.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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 (PMID: 19206169, 20186801, 25463315). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 13978). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 16474404, 17483702). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 501 of the BRAF protein (p.Glu501Gly).

#	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: Sep 29, 2024

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