chr7-140749365-A-C

Position:

• chr7-140749365-A-C

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1_Very_Strong PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):​c.2034T>G​(p.Asp678Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 1.87

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]

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13981
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9008 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-140749365-A-C is Pathogenic according to our data. Variant chr7-140749365-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 162797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140749365-A-C is described in Lovd as [Pathogenic]. Variant chr7-140749365-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.2034T>G	p.Asp678Glu	missense_variant	17/20	ENST00000644969.2
BRAF	NM_004333.6	c.1914T>G	p.Asp638Glu	missense_variant	16/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.2034T>G	p.Asp678Glu	missense_variant	17/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1914T>G	p.Asp638Glu	missense_variant	16/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic [(HGMD]; This variant is associated with the following publications: (PMID: 27171548, 30141192, 23093928, 25525159, 19206169, 18413255, 21063443, 30556322, 32369273, 33040082, 31069529, 34643321) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Sep 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 16, 2018	- -

Cardio-facio-cutaneous syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 27, 2013	The Asp638Glu variant in BRAF has been reported to have occurred de novo in two individuals with clinical features of Cardio-facio-cutaneous syndrome (Sarkozy 2 009, Kleefstra 2011). Another variant at this nucleotide position resulting in the same amino acid residue change has also been reported in two individuals wit h clinical features of Cardio-facio-cutaneous syndrome including one de novo occ urrence (Sarkozy 2009, Rauen 2006). This variant was not identified in large po pulation studies. Studies have shown that the Asp638Glu variant impacts protein function (Rodriguez-Viciana 2008). In summary, the Asp638Glu variant meets our c riteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upo n its de novo occurrence in affected individuals, low allele frequency in the ge neral population, and supporting functional evidence. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2017

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). 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. ClinVar contains an entry for this variant (Variation ID: 162797). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (PMID: 16804887, 18039235, 22495831). 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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 638 of the BRAF protein (p.Asp638Glu). -

Noonan syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - CFC International

-

Variant interpreted as Pathogenic and reported on 10-13-2014 by Lab or GTR ID 26957. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Pathogenic	3.0	.;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.95
Polyphen		1.0	.;.;D;.
MutPred		0.98		Loss of phosphorylation at Y640 (P = 0.124);.;Loss of phosphorylation at Y640 (P = 0.124);.;
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs180177042; hg19: chr7-140449165;