chr7-140753339-G-C

Position:

• chr7-140753339-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4_Moderate PS3 PS2 PM2 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID:19206169). Additionally, the variant is located in BRAF, 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_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603019/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1916C>G	p.Thr639Arg	missense_variant	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1796C>G	p.Thr599Arg	missense_variant	15/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1916C>G	p.Thr639Arg	missense_variant	16/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1796C>G	p.Thr599Arg	missense_variant	15/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (PMID: 19206169, 28650561, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19206169, PS3). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Thr599Ile) has been reported as pathogenic (VCV000040388.5, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	The T599R pathogenic variant in the BRAF gene has been reported previously in association with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al., 2008; Sarkozy et al., 2014). Functional studies indicate that the T599R variant results in increased foci formation and increased phosphorylation of the ERK and MEK proteins (Sarkozy et al., 2014). The T599R variant is not observed in large population cohorts (Lek et al., 2016). The T599R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (F595L, G596V, L597V, V600G, K601Q, K601I) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T599R as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -

RASopathy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Mar 24, 2020

The c.1796C>G (p.Thr599Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed in 3 probands diagnosed with cardiofaciocutaneous syndrome (PS4_Moderate; PMIDs: 19206169, 28650561; Otto-von-Guericke-Universität Magdeburg internal communication). In two of these patients, as well as one proband with phenotypic features suggestive of a RASopathy but no clinical diagnosis, the variant occurred de novo; parentage was confirmed in 2 of these cases (PS2_VS; PMIDs: 19206169, 28650561; GeneDx internal data, SCV000329761.7). The variant occurs in the CR3 activation domain of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). In vitro functional studies provide some evidence that the p.Thr599Arg variant may impact protein function (PS3; PMID: 19206169). Additionally, the variant is located in BRAF, 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_VeryStrong, PS3, PS4_Moderate, PM1, PM2, PP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	.;.;D;.
Eigen	Benign	0.079
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	-0.65	.;.;N;.
PrimateAI	Pathogenic	0.87	D
REVEL	Pathogenic	0.69
Polyphen		0.032	.;.;B;.
MutPred		0.85		Gain of MoRF binding (P = 0.0108);.;Gain of MoRF binding (P = 0.0108);.;
MVP		0.98
MPC		1.2
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.86

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: rs121913375; hg19: chr7-140453139; COSMIC: COSV56167356;