rs121913338

Variant names:

• chr7-140753354-T-A
• rs121913338
• NM_001374258.1:c.1901A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-140753354-T-A
• chr7-140753354-T-C
• chr7-140753354-T-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PP2 PM1 PM2 PS2 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) 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). 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): PS2, PS4_Moderate, PM1, PM2, PP2, PP3, LINK:https://erepo.genome.network/evrepo/ui/classification/CA16602425/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 7.94
• Publications: 486 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 12 ACMG points.

• PS2: 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.1901A>T	p.Asp634Val	missense_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1781A>T	p.Asp594Val	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.1901A>T	p.Asp634Val	missense_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1781A>T	p.Asp594Val	missense_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:1 Uncertain:1

Dec 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported to affect BRAF protein function (PMID: 18413255, 20141835, 19376813, 19735675). This variant has been observed in an individual affected with cardio-facio-cutaneous syndrome (PMID: 18413255). ClinVar contains an entry for this variant (Variation ID: 375946). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 594 of the BRAF protein (p.Asp594Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine.

May 18, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) 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). 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): PS2, PS4_Moderate, PM1, PM2, PP2, PP3,

Cardio-facio-cutaneous syndrome Uncertain:1

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.99
DEOGEN2	Benign	0.0	.;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	0.0	.;.;H;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.0	.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0
Mutation Taster		=9/91	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: rs121913338; hg19: chr7-140453154; COSMIC: COSV56283955;