7-140753354-T-C

Variant names:

• chr7-140753354-T-C
• rs121913338
• NM_001374258.1:c.1901A>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_004333.6(BRAF):​c.1781A>G​(p.Asp594Gly) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D594V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 7.94

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140753354-T-A is described in Lovd as [Pathogenic].
• 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, 0.986
• PP5: Variant 7-140753354-T-C is Pathogenic according to our data. Variant chr7-140753354-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13972.We mark this variant Likely_pathogenic, oryginal submissions are: {other=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1901A>G	p.Asp634Gly	missense_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1781A>G	p.Asp594Gly	missense_variant	Exon 15 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1901A>G	p.Asp634Gly	missense_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1781A>G	p.Asp594Gly	missense_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lung adenocarcinoma Pathogenic:1

-

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 09, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A BRAF c.1781A>G (p.Asp594Gly) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in the ClinVar database as a variant of uncertain significance in a germline state by one submitter (ClinVar Variation ID: 13972) and it has been reported in numerous types of cancers in the cancer database COSMIC (Genomic Mutation ID: COSV56065695). This variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. The BRAF c.1781A>G (p.Asp594Gly) variant occurs at a highly conserved residue within the CR3 activation segment, amino acids 594-627, of BRAF that is defined as a critical functional domain (Wellbrock C, et al., PMID: 15520807; Gelb BD, et al., PMID: 29493581). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies show that this kinase-dead BRAF variant has a higher dimerization potential with CRAF as compared with WT BRAF and it has the ability to bypass autoinhibitory autophosphorylation which results in a sustained mitogen-activated protein kinase (MAPK) signaling (Cope NJ et al., PMID: 31929109). The BRAF gene is defined by the ClinGen RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD, et al., PMID: 29493581). Other variants in the same codon, c.1782T>G (p.Asp594Glu) and c.1781A>T (p.Asp594Val), have been reported and are considered pathogenic (including by an expert panel), likely pathogenic, or uncertain significance (ClinVar IDs: 375946, 375944). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation and gene-specific practices from the ClinGen Criteria Specification Registry (Leon-Quintero FZ et al., PMID: 39434542), the BRAF c.1781A>G (p.Asp594Gly) variant is classified as pathogenic. -

Non-small cell lung carcinoma Pathogenic:1

Jun 11, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported as a somatic change in large intestine, skin, end ometrium, stomach, and ovary (COSMIC, Fransen 2004) and has been observed in up to 11% of BRAF mutant positive lung adenocarcinoma (Paik 2011). -

Non-Hodgkin lymphoma Pathogenic:1

Nov 17, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

RASopathy Uncertain:1

Aug 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with glycine at codon 594 of the BRAF protein (p.Asp594Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13972). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. Experimental studies have shown that this variant affects BRAF function (PMID: 23352452, 29595366). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.5	.;.;M;.
PrimateAI	Pathogenic	0.87	D
REVEL	Pathogenic	0.99
Polyphen		0.99	.;.;D;.
MutPred		0.97		Gain of methylation at K591 (P = 0.0513);.;Gain of methylation at K591 (P = 0.0513);.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121913338; hg19: chr7-140453154; COSMIC: COSV56065695;