7-140801533-A-G

Variant names:

• chr7-140801533-A-G
• rs397516903
• NM_001374258.1:c.739T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP3 PP2 PM1 PM6 PM2 PS1 PS3

This summary comes from the ClinGen Evidence Repository: The c.739T>C (p.Phe247Leu) variant in BRAF has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR Lab ID: 26957; ClinVar SCV000207748.12). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that the p.Phe247Leu variant may impact protein function (PS3; PMID:28512244). The c.739T>C variant results in the same amino acid change as the previously established pathogenic c.741T>G (p.Phe247Leu) variant (PS1; ClinVar ID 55793). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). The variant 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). Computational prediction tools and conservation analysis suggest that the p.Phe247Leu variant may impact the protein (PP3). 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): PM6, PM2, PS3, PS1, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA295904/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 9.27
• Publications: 12 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• 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
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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.
• PM6: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004333.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.739T>C	p.Phe247Leu	missense	Exon 6 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.739T>C	p.Phe247Leu	missense	Exon 6 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.739T>C	p.Phe247Leu	missense	Exon 6 of 19	NP_001361173.1	A0A2U3TZI2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.739T>C	p.Phe247Leu	missense	Exon 6 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.739T>C	p.Phe247Leu	missense	Exon 6 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.739T>C	p.Phe247Leu	missense	Exon 6 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000161 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiofaciocutaneous syndrome 1 (1)
1	-	-	Noonan syndrome (1)
1	-	-	Noonan syndrome 7 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	not provided (1)
1	-	-	RASopathy (1)
-	-	-	Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		0.81	P
Vest4		0.77
MutPred		0.69		Loss of helix (P = 0.028)
MVP		0.95
MPC		1.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.95
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516903; hg19: chr7-140501333;