NM_001374258.1:c.1526G>A

Variant names:

• chr7-140781602-C-T
• rs121913355
• NM_001374258.1:c.1526G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4 PM1 PS3_Supporting PS2 PP3 PP2 PM2_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
• Clinical Significance: Pathogenic reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 7.89

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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	c.1526G>A	p.Gly509Glu	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	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	c.1526G>A	p.Gly509Glu	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1406G>A	p.Gly469Glu	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:5

-

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

- -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

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. -

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 -

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) -

Jul 27, 2014

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 -

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. -

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) -

Cardio-facio-cutaneous syndrome Pathogenic:2 Other:1

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 . -

-

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. -

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. -

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

- -

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 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	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;M;.
PrimateAI	Pathogenic	0.94	D
REVEL	Pathogenic	0.92
Polyphen		1.0	.;.;D;.
MutPred		0.99		Loss of MoRF binding (P = 0.0591);.;Loss of MoRF binding (P = 0.0591);.;
MVP		0.98
MPC		2.4
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs121913355; hg19: chr7-140481402; COSMIC: COSV56065622;