NM_001374258.1:c.2255C>T

Variant names:

• chr7-140734763-G-A
• rs727502904
• NM_001374258.1:c.2255C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001374258.1(BRAF):​c.2255C>T​(p.Ala752Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000786 in 1,272,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A752T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 3 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr7-140734764-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 802373.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.2255C>T	p.Ala752Val	missense	Exon 19 of 20	NP_001361187.1	A0A2R8Y8E0
	BRAF	NM_004333.6	MANE Select	c.2135C>T	p.Ala712Val	missense	Exon 18 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.2255C>T	p.Ala752Val	missense	Exon 19 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.2255C>T	p.Ala752Val	missense	Exon 19 of 20	ENSP00000496776.1	A0A2R8Y8E0
	BRAF	ENST00000646891.2	MANE Select	c.2135C>T	p.Ala712Val	missense	Exon 18 of 18	ENSP00000493543.1	P15056
	BRAF	ENST00000288602.11	TSL:1	c.2255C>T	p.Ala752Val	missense	Exon 19 of 19	ENSP00000288602.7	A0A2U3TZI2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 7.86e-7 AC: 1 AN: 1272034 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 626468

African (AFR) AF: 0.00 AC: 0 AN: 27686

American (AMR) AF: 0.00 AC: 0 AN: 26308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20764

East Asian (EAS) AF: 0.00 AC: 0 AN: 32230

South Asian (SAS) AF: 0.00 AC: 0 AN: 49274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5088

European-Non Finnish (NFE) AF: 9.86e-7 AC: 1 AN: 1013848

Other (OTH) AF: 0.00 AC: 0 AN: 51366

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	N
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
REVEL	Uncertain	0.40
Polyphen		0.16	B
MutPred		0.34		Loss of disorder (P = 0.0421)
MVP		0.75
MPC		1.4
ClinPred		0.68	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.68
Mutation Taster		=16/84	disease causing

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: rs727502904; hg19: chr7-140434563;