chr7-140781602-C-A

Variant names:

• chr7-140781602-C-A
• rs121913355
• NM_001374258.1:c.1526G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001374258.1(BRAF):​c.1526G>T​(p.Gly509Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89
• Publications: 710 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

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001374258.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140781602-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13974.Status of the report is reviewed_by_expert_panel, 3 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: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-140781602-C-A is Pathogenic according to our data. Variant chr7-140781602-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 44803.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.1526G>T	p.Gly509Val	missense	Exon 12 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.1406G>T	p.Gly469Val	missense	Exon 11 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.1526G>T	p.Gly509Val	missense	Exon 12 of 19	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.1526G>T	p.Gly509Val	missense	Exon 12 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.1406G>T	p.Gly469Val	missense	Exon 11 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.1526G>T	p.Gly509Val	missense	Exon 12 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1

Dec 30, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.96
Polyphen		1.0	D
MutPred		0.96		Gain of sheet (P = 0.0827)
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.94
Mutation Taster		=0/100	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: rs121913355; hg19: chr7-140481402; COSMIC: COSV56062352;