rs397507483

Variant names:

• chr7-140753348-C-A
• rs397507483
• NM_001374258.1:c.1907G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-140753348-C-A
• chr7-140753348-C-G
• chr7-140753348-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP2 PP3 PM2 PM1 PS3 PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). 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): PM6_Strong, PS3, PM2, PP2, PP3, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220161/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:2
• Conservation: PhyloP100: 7.83
• Publications: 87 publications found

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

ACMG classification

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

• PS3: 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.
• PM6: 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	c.1907G>T	p.Gly636Val	missense_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1787G>T	p.Gly596Val	missense_variant	Exon 15 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1907G>T	p.Gly636Val	missense_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1787G>T	p.Gly596Val	missense_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:3

Aug 20, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PM2,PM6_Strong,PP2,PP3,PP4. -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardiofaciocutaneous syndrome (MIM#115150), LEOPARD syndrome (MIM#3613707) and Noonan syndrome (MIM#7613706). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The germline variant has been reported multiple times as likely pathogenic and pathogenic in individuals with RASopathies, including Noonan syndrome (NS) and cardiofaciocutaneous (CFC) syndrome (ClinVar, PMID: 33040082). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) in a research setting (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2013

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly596Val (GGT>GTT): c.1787 G>T in exon 15 of the BRAF gene (NM_004333.4). The G596V mutation in the BRAF gene has been previously reported in at least 4 unrelated patients with Cardio-Facio-Cutaneous syndrome (Rodriguez-Viciana et al., 2006). This mutation falls within the activation loop located within the third conserved region of the BRAF protein. The G596V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:3

-

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines -

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1787G>T (p.Gly596Val) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16439621, 25463315, Partners LMM and GeneDx internal data; GTR ID's: 21766, 26957; ClinVar SCV000197137, SCV000057237). In vitro functional studies provide some evidence that the p.Gly596Val variant may impact protein function (PS3; PMID 18413255). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Gly596Val variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). 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): PM6_Strong, PS3, PM2, PP2, PP3, PM1. -

Jul 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 596 of the BRAF protein (p.Gly596Val). 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: 16439621, 25463315). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40387). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRAF function (PMID: 16439621, 18413255, 19376813). -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1 Other:1

-

GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 12-03-2010 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. -

Sep 10, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly596Val variant has been identified in 7 individuals with clinical feature s of Cardio-facio-cutaneous syndrome (CFC) and 3 individuals with clinical featu res of Noonan syndrome (Rodriguez-Viciana 2006, Yoon 2007, Rodriguez-Viciana 200 8, LMM unpublished data). It was absent from large population studies. In-vitro functional studies provide some evidence that the Gly596Val variant may impact p rotein function (Rodrigues-Viciana 2006). Furthermore, animal models in zebrafis h have shown that this variant causes severe developmental abnormalities (Anasta saki 2009). In summary, this variant meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/). -

Inborn genetic diseases Pathogenic:1

Jan 10, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.3	.;.;M;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
REVEL	Pathogenic	0.99
Polyphen		1.0	.;.;D;.
MutPred		0.99		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		1.0
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397507483; hg19: chr7-140453148;