7-140753336-A-T

Variant names:

• chr7-140753336-A-T
• rs113488022
• NM_001374258.1:c.1919T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_004333.6(BRAF):​c.1799T>A​(p.Val600Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18 U:2 O:6
• Conservation: PhyloP100: 9.24

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 Likely_pathogenic. Variant got 8 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, 0.883
• PP5: Variant 7-140753336-A-T is Pathogenic according to our data. Variant chr7-140753336-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13961.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, other=4, Uncertain_significance=1, Pathogenic=3, not_provided=1}. Variant chr7-140753336-A-T is described in Lovd as [Likely_pathogenic]. Variant chr7-140753336-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1919T>A	p.Val640Glu	missense_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1799T>A	p.Val600Glu	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.1919T>A	p.Val640Glu	missense_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1799T>A	p.Val600Glu	missense_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251260 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460618 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726662

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18 Uncertain:2 Other:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Sylvester Comprehensive Cancer Center, University of Miami

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

BRAF V600E variant is involved in encoding cytoplasmic serine/threonine kinases within the MAPK pathway. The NCCN Guidelines state that BRAF mutations are an indicative prognostic marker with poor clinical outcome. It it recommended to do baseline genomic genotyping of the patient's primary or metastatic tumor tissue at diagnosis if the patient is stage IV. BRAF V600E is mutated in about 15% of all cancers (El-Osta et. al, 2011). Frequency of all RAF mutations is 2.2% within pancreatic cancer, where BRAF V600E is one of the more common variants, and is actionable (Hendifar et al., 2021) -

Melanoma Pathogenic:1 Other:2

May 15, 2018

CIViC knowledgebase, Washington University School of Medicine

Significance: -

Review Status: criteria provided, single submitter

Collection Method: curation

Combination treatment of BRAF inhibitor dabrafenib and MEK inhibitor trametinib is recommended for adjuvant treatment of stage III or recurrent melanoma with BRAF V600E mutation detected by the approved THxID kit, as well as first line treatment for metastatic melanoma. The treatments are FDA approved based on studies including the Phase III COMBI-V, COMBI-D and COMBI-AD Trials. Combination therapy is now recommended above BRAF inhibitor monotherapy. Cutaneous squamous-cell carcinoma and keratoacanthoma occur at lower rates with combination therapy than with BRAF inhibitor alone. -

Nov 01, 2018

Wagner Lab, Nationwide Children's Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: curation

Vemurafenib and cobimetinib combination is an FDA approved first line treatment for BRAF V600E mutant metastatic melanoma based on clinical data including the Phase III coBRIM trial. The cobas 4800 BRAF V600 Mutation Test is approved as an FDA companion test for Cotellic (cobimetinib) in combination with Zelboraf (vemurafenib). -

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cystic epithelial invagination containing papillae lined by columnar epithelium Pathogenic:2

May 07, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 07, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lymphangioma Pathogenic:1

Feb 09, 2022

James Bennett Lab, Seattle Childrens Research Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The Val600Glu variant in BRAF was observed at very low levels (VAF 0.3-2%) in lymphatic malformation tissue from three unrelated individuals using high depth NGS (VANseq), confirmatory digital droplet PCR, and BRAF V600E immunohistochemistry. -

Papillary thyroid carcinoma Pathogenic:1

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Vascular malformation Pathogenic:1

Oct 22, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRAF c.1799T>A (p.Val600Glu) variant was identified at an allelic fraction consistent with somatic origin. This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs in 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). The BRAF c.1799T>A (p.Val600Glu) variant in a somatic state has been reported in multiple individuals affected with sporadic vascular malformations, brain arteriovenous malformation (BAVM) and spinal arteriovenous malformation (SAVM) (Hong T, et al., PMID: 30544177; Al-Olabi L, et al., PMID: 29461977; Goss JA, et al., PMID: 31891627; Li H, et al., PMID: 34530633). The BRAF c.1799T>A (p.Val600Glu) variant has been reported in the ClinVar database as pathogenic by numerous submitters (ClinVar ID: 13961). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies show constitutively active kinase activity (Rodriguez-Viciana P, et al., PMID: 16439621; Sarkozy A, et al., PMID:19206169; Al-Olabi L, et al., PMID: 29461977). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, this variant is classified as pathogenic. -

Astrocytoma, low-grade, somatic Pathogenic:1

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Carcinoma of colon Pathogenic:1

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple myeloma Pathogenic:1

Aug 31, 2019

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nephroblastoma Pathogenic:1

Feb 15, 2019

Pediatric Oncology, Johns Hopkins University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant neoplastic disease Pathogenic:1

-

Investigational Cancer Therapeutics, MD Anderson Cancer Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cerebral arteriovenous malformation Pathogenic:1

-

Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Non-small cell lung carcinoma Pathogenic:1

May 29, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nongerminomatous germ cell tumor Pathogenic:1

Sep 04, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype Pathogenic:1

May 23, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ASSESSED FOR SOMATIC SAMPLE ONLY. FOR ANY GERMLINE INDICATION, PLEASE REASSESS. -

RASopathy Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 600 of the BRAF protein (p.Val600Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been reported as a known somatic variant in various cancers but has not been reported in the literature in individuals affected with germline BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13961). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. This variant disrupts the p.Val600 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Thyroid gland undifferentiated (anaplastic) carcinoma Other:1

Feb 01, 2024

National Institute of Cancer Research, National Health Research Institutes

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

This mutation has been reported in anaplastic thyroid cancers (PMID: 29615459; PMID: 29742974; PMID: 33029242). The anaplastic thyroid cancer patients with this mutation had a median progression free survival of 6.7 months (PMID: 37059834). -

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

- -

Colorectal cancer Other:1

Feb 28, 2019

CIViC knowledgebase, Washington University School of Medicine

Significance: -

Review Status: criteria provided, single submitter

Collection Method: curation

BRAF V600E was associated with worse prognosis in Phase II and III colorectal cancer, with a stronger effect in MSI-Low or MSI-Stable tumors. In metastatic CRC, V600E was associated with worse prognosis, and meta-analysis showed BRAF mutation in CRC associated with multiple negative prognostic markers. -

Cardio-facio-cutaneous syndrome Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.83	.;.;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.65	.;.;N;.
PrimateAI	Pathogenic	0.89	D
REVEL	Pathogenic	0.93
Polyphen		0.97	.;.;D;.
MutPred		0.71		Gain of disorder (P = 0.0057);.;Gain of disorder (P = 0.0057);.;
MVP		0.99
MPC		2.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.95

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: rs113488022; hg19: chr7-140453136; COSMIC: COSV56056643;