rs121913338

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3 PP2 PS2 PS4_Moderate PM1

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:3 U:2
• Conservation: PhyloP100: 7.94

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 12 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1901A>T	p.Asp634Val	missense_variant	16/20	ENST00000644969.2
BRAF	NM_004333.6	c.1781A>T	p.Asp594Val	missense_variant	15/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1901A>T	p.Asp634Val	missense_variant	16/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1781A>T	p.Asp594Val	missense_variant	15/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:1 Uncertain:1

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	May 18, 2020	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, -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2018	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. -

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Neoplasm of the large intestine Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Cardio-facio-cutaneous syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

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
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
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	.;.;D;.
MutPred		0.92		Gain of methylation at K591 (P = 0.0382);.;Gain of methylation at K591 (P = 0.0382);.;
MVP		0.98
MPC		2.4
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913338; hg19: chr7-140453154; COSMIC: COSV56283955;