7-140781602-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS4PS3_SupportingPM1PS2PP3PP2PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). 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). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA279970/MONDO:0015280/049

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19O:1

Conservation

PhyloP100: 7.89

Publications

710 publications found

Variant links:

Genes affected

BRAF (HGNC:1097): (B-Raf proto-oncogene, serine/threonine kinase) This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]

BRAF Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
cardiofaciocutaneous syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
LEOPARD syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Noonan syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
anaplastic astrocytoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BRAF links:

ENSG00000289788 (HGNC:):

ENSG00000289788 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1 link	c.1526G>A	p.Gly509Glu	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1406G>A	p.Gly469Glu	missense_variant	Exon 11 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.1526G>A	p.Gly509Glu	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2 link	c.1406G>A	p.Gly469Glu	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

251420

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727174

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111912

Other (OTH)

AF:

0.00

AC:

AN:

60392

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 1

Pathogenic:7

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Aug 18, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel and by clinical laboratories in ClinVar. It has also reported in the literature in individuals with cardiofaciocutaneous syndrome (PMIDs: 35418823, 30141192, 16474404); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband by trio analysis (parental status confirmed). Additional information: Variant is predicted to result in a missense amino acid change from Gly to Glu; This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER); Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150), and Noonan syndrome 7 (MIM#613706) (PMIDs: 28783719, 29540830).

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2019

Genetic Laboratory, Lianyungang Maternal and Child Health Hospital Affiliated to Kangda College of Nanjing Medical University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Oct 07, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581, 29493581). Missense variant. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16474404). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013974 /PMID: 16474404 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16474404, 18042262). Different missense changes at the same codon (p.Gly469Ala, p.Gly469Arg, p.Gly469Leu, p.Gly469Ser, p.Gly469Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013970, VCV000013971, VCV000044803, VCV000177775, VCV000375950, VCV000376072 /PMID: 24303953, 36002837). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Dec 25, 2017

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.

Mar 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Pathogenic:3

Jun 23, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3

Jul 27, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 13, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on B-Raf activity and MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23093928, 34573299, 30141192, 34184824, 29907801, 18042262, 16474404, 16439621, 19206169, 24803665, 33040082)

RASopathy

Pathogenic:3

Sep 17, 2024

ClinGen RASopathy Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). 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). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 469 of the BRAF protein (p.Gly469Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardiofaciocutaneous syndrome (PMID: 16439621, 16474404, 18042262, 19206169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13974). 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%. For these reasons, this variant has been classified as Pathogenic.

Baylor Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Variant classified using ACMG guidelines

Cardio-facio-cutaneous syndrome

Pathogenic:2Other:1

Dec 09, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251520 control chromosomes. c.1406G>A has been reported in the literature as a de-novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome (example, Nihori_2006, Smalley_2009, Sarkozy_2009, Pandit_2007, Schultz_2008, Greaves_2013, Ciara_2015, Lee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of ERK activation by trigerring C-RAF activity as a distinct mechanism of action (Wan_2004). Five clinical diagnostic laboratories and one expert panel (ClinGen RASopathy panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

GenomeConnect - CFC International

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.

Jul 26, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this variant was reported to have occurred de novo in three of those individuals. Therefore, this variant is highly likely to be pathogenic .

not specified

Pathogenic:1

Mar 10, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Noonan syndrome 7

Pathogenic:1

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Noonan syndrome 1

Pathogenic:1

Molecular Genetics, Centre for Human Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Mar 05, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

.;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;.;M;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

0.0

.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.

Vest4

0.0

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over