7-140781602-C-T

Position:

• chr7-140781602-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS2 PM1 PP3 PP2 PM2_Supporting PS4 PS3_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:25 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]

(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/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1526G>A	p.Gly509Glu	missense_variant	12/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1406G>A	p.Gly469Glu	missense_variant	11/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1526G>A	p.Gly509Glu	missense_variant	12/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1406G>A	p.Gly469Glu	missense_variant	11/18		NM_004333.6	ENSP00000493543	P4
	ENST00000700122.1	n.502+6734C>T		intron_variant, non_coding_transcript_variant

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:25 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 25, 2017	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

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2020	PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 27, 2014	- -

RASopathy Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 18, 2023	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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13974). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2011	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 . -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2019	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. -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	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. -

Noonan syndrome 7 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

-

- -

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Squamous cell carcinoma of the skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 10, 2017

- -

Multiple myeloma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Transitional cell carcinoma of the bladder Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 05, 2021

- -

Neoplasm of the large intestine Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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;.
MutationTaster	Benign	1.0	D
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;