7-140749365-A-C

Variant names:

• chr7-140749365-A-C
• rs180177042
• NM_001374258.1:c.2034T>G

Variant summary

Our verdict is Pathogenic. The variant received 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 the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 1.87
• Publications: 30 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 23 ACMG points.

• PS1: Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.
• 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 VariationId is 162797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.2034T>G	p.Asp678Glu	missense	Exon 17 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.1914T>G	p.Asp638Glu	missense	Exon 16 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.2034T>G	p.Asp678Glu	missense	Exon 17 of 19	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.2034T>G	p.Asp678Glu	missense	Exon 17 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.1914T>G	p.Asp638Glu	missense	Exon 16 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.2034T>G	p.Asp678Glu	missense	Exon 17 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Dec 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Aug 16, 2018

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2018

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardio-facio-cutaneous syndrome Pathogenic:2

Aug 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 14, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome 7 Pathogenic:1

Sep 07, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (T>G) at position 1914 of the coding sequence of the BRAF gene that results in a aspartic acid to glutamic acid amino acid change at residue 638 of the B-Raf proto-oncogene, serine/threonine kise protein. The 638 residue falls in the kise domain (PMID: 18413255) which plays a critical role in BRAF function. This is a previously reported variant (ClinVar 162797) that has been observed in individuals affected by Costello syndrome (PMID: 16804887, 31069529) and cardiofaciocutaneous syndrome (PMID: 19206169, 37138575, 20859831, 21063443, 33040082, 27391121, 29095811, 22495831, 18039235, 37510243, 27940666, 31217210, 35524774, 34573299, 32369273), several of which were confirmed de novo (PMID: 19206169, 37138575, 20859831, 21063443). This variant is absent from the gnomAD population database (0/~250,000 alleles). Multiple bioinformatic tools predict that this Asp to Glu amino acid change would be damaging, and the Asp638 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant demonstrate impaired kise activity (PMID: 18413255). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP2, PP3, PS1, PS3

Inborn genetic diseases Pathogenic:1

Jan 05, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRAF-related disorder Pathogenic:1

Sep 12, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.95 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=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: VCV000162797 /PMID: 19206169 /3billion dataset). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 16804887, 18039235, 22495831). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Melanoma Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM6,PS3,PM5,PM2,PP3

RASopathy Pathogenic:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 (CFC) and Costello syndrome (PMID: 16804887, 18039235, 22495831). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 162797). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 18413255). For these reasons, this variant has been classified as Pathogenic.

Noonan syndrome 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 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 v4.9

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
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		1.9
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.95
Polyphen		1.0	D
MutPred		0.98		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
Mutation Taster		=12/88	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs180177042; hg19: chr7-140449165; COSMIC: COSV106088334;