7-140753346-G-C

Variant names:

• chr7-140753346-G-C
• rs121913369
• NM_001374258.1:c.1909C>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004333.6(BRAF):​c.1789C>G​(p.Leu597Val) variant causes a missense change. 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 (★★). ClinVar reports functional evidence for this variant: "SCV002526401: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:19206169)" - PS3_supporting." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L597P) has been classified as Uncertain significance. The gene BRAF is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 4.96
• Publications: 167 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

Specifications for BRAF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002526401: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19206169)" - PS3_supporting.; SCV000204067: "In vitro functional studies suggest that the p.Leu597Val variant may impact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009)."; SCV002555623: Ras/MAPK dysregulation in development has been demonstrated to cause a skeletal myopathy in an activating Braf-L597V mouse model for cardio-facio-cutaneous syndrome (Maeda_2021).; SCV003440223: Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169).
• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140753345-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13968.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to LEOPARD syndrome 3, Costello syndrome, Noonan syndrome 7, Noonan syndrome-like disorder with loose anagen hair, cardiofaciocutaneous syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, anaplastic astrocytoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-140753346-G-C is Pathogenic according to our data. Variant chr7-140753346-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1909C>G	p.Leu637Val	missense	Exon 16 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.1789C>G	p.Leu597Val	missense	Exon 15 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.1909C>G	p.Leu637Val	missense	Exon 16 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.1909C>G	p.Leu637Val	missense	Exon 16 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.1789C>G	p.Leu597Val	missense	Exon 15 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.1909C>G	p.Leu637Val	missense	Exon 16 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Cardio-facio-cutaneous syndrome (2)
2	-	-	Non-small cell lung carcinoma (2)
2	-	-	Noonan syndrome 7 (2)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome (1)
1	-	-	RASopathy (1)
-	-	-	Noonan syndrome 1 (1)
-	-	-	Noonan syndrome 7;C3150971:LEOPARD syndrome 3;CN029449:Cardiofaciocutaneous syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.5	L
PhyloP100		5.0
PrimateAI	Pathogenic	0.80	D
REVEL	Pathogenic	0.80
Polyphen		0.93	P
MutPred		0.95		Gain of sheet (P = 0.0827)
MVP		0.99
MPC		1.6
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.93
gMVP		0.88
Mutation Taster		=24/76	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: rs121913369; hg19: chr7-140453146; COSMIC: COSV56128388;