NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe) AND RASopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 28, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001172276.13

Allele description [Variation Report for NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe)]

NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe)

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.1455G>C (p.Leu485Phe)

HGVS:

NC_000007.14:g.140778053C>G
NG_007873.3:g.151712G>C
NM_001354609.2:c.1455G>C
NM_001374244.1:c.1575G>C
NM_001374258.1:c.1575G>C
NM_001378467.1:c.1464G>C
NM_001378468.1:c.1455G>C
NM_001378469.1:c.1389G>C
NM_001378470.1:c.1353G>C
NM_001378471.1:c.1344G>C
NM_001378472.1:c.1299G>C
NM_001378473.1:c.1299G>C
NM_001378474.1:c.1455G>C
NM_001378475.1:c.1191G>C
NM_004333.6:c.1455G>CMANE SELECT
NP_001341538.1:p.Leu485Phe
NP_001361173.1:p.Leu525Phe
NP_001361187.1:p.Leu525Phe
NP_001365396.1:p.Leu488Phe
NP_001365397.1:p.Leu485Phe
NP_001365398.1:p.Leu463Phe
NP_001365399.1:p.Leu451Phe
NP_001365400.1:p.Leu448Phe
NP_001365401.1:p.Leu433Phe
NP_001365402.1:p.Leu433Phe
NP_001365403.1:p.Leu485Phe
NP_001365404.1:p.Leu397Phe
NP_004324.2:p.Leu485Phe
NP_004324.2:p.Leu485Phe
LRG_299t1:c.1455G>C
LRG_299:g.151712G>C
NC_000007.13:g.140477853C>G
NM_004333.4:c.1455G>C
NM_004333.6(BRAF):c.1455G>CMANE SELECT
P15056:p.Leu485Phe

Protein change:

L397F; LEU485PHE

Links:

UniProtKB: P15056#VAR_026115; OMIM: 164757.0015; dbSNP: rs180177036

NCBI 1000 Genomes Browser:

rs180177036

Molecular consequence:

NM_001354609.2:c.1455G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.1575G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.1575G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.1464G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.1455G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.1389G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.1353G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.1344G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.1299G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.1299G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.1455G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.1191G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.1455G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001335323	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Feb 28, 2020)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 18413255, 19206169, 16474404 Citation Link,
SCV003440224	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16474404, 19206169, 28524057, 18413255, 28492532
SCV004123092	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 1, 2023)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001335323

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Feb 28, 2020)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV003440224

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

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

SCV004123092

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 1, 2023)

germline

research

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	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.

Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, Okamoto N, Hennekam RC, Gillessen-Kaesbach G, Wieczorek D, Kavamura MI, Kurosawa K, Ohashi H, Wilson L, Heron D, Bonneau D, Corona G, Kaname T, Naritomi K, Baumann C, Matsumoto N, Kato K, et al.

Nat Genet. 2006 Mar;38(3):294-6. Epub 2006 Feb 12.

PubMed [citation]

PMID:: 16474404

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 ClinGen RASopathy Variant Curation Expert Panel, SCV001335323.1

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

Description

The c.1455G>C (p.Leu485Phe) variant in BRAF is absent from gnomAD (PM2). It has been detected in at least 4 patients with clinical features of a RASopathy, 1 of which was reported as a de novo case with parentage confirmation (PS4_Moderate; PS2; 19206169, 16474404, SCV000197149.4). In vitro functional studies provide some evidence that the p.L485F variant may impact protein function (PS3; PMID: 18413255). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Additionally, computational prediction tools and conservation analysis suggest that this variant may affect the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PS2, PS3, PM2, PP2, PP3.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003440224.2

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 485 of the BRAF protein (p.Leu485Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16474404, 19206169, 28524057). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13975). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). For these reasons, this variant has been classified as Pathogenic.

#	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

From Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand, SCV004123092.1

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

Last Updated: Oct 13, 2024

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