7-140777013-C-A

Variant names:

• chr7-140777013-C-A
• rs606231228
• NM_001374258.1:c.1713G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_004333.6(BRAF):​c.1593G>T​(p.Trp531Cys) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.88

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• 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, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 7-140777013-C-A is Pathogenic according to our data. Variant chr7-140777013-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 265358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1713G>T	p.Trp571Cys	missense_variant	Exon 14 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1593G>T	p.Trp531Cys	missense_variant	Exon 13 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1713G>T	p.Trp571Cys	missense_variant	Exon 14 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1593G>T	p.Trp531Cys	missense_variant	Exon 13 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23093928, 26633542, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581, 30290804, 19206169, 33644862, 33040082) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.65	.;.;N;.
PrimateAI	Pathogenic	0.94	D
REVEL	Pathogenic	0.86
Polyphen		1.0	.;.;D;.
MutPred		0.94		Gain of catalytic residue at S535 (P = 0.1494);.;Gain of catalytic residue at S535 (P = 0.1494);.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98

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: rs606231228; hg19: chr7-140476813; COSMIC: COSV56398551; COSMIC: COSV56398551;