7-140753336-A-T

Position:

chr7-140753336-A-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18U:1O:6

Conservation

PhyloP100: 9.24

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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 gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with 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 [Likely_pathogenic]. Clinvar id is 13961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.1919T>A	p.Val640Glu	missense_variant	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.1799T>A	p.Val600Glu	missense_variant	15/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.1919T>A	p.Val640Glu	missense_variant	16/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2 linkuse as main transcript	c.1799T>A	p.Val600Glu	missense_variant	15/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251260

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

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:

AN:

1460618

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726662

show subpopulations

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.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Uncertain:1Other:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jul 11, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Sylvester Comprehensive Cancer Center, University of Miami	-	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) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Melanoma

Pathogenic:1Other:2

-, criteria provided, single submitter	curation	Wagner Lab, Nationwide Children's Hospital	May 15, 2018	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. -
-, criteria provided, single submitter	curation	CIViC knowledgebase, Washington University School of Medicine	May 15, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 04, 2014	- -

Cystic epithelial invagination containing papillae lined by columnar epithelium

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	May 07, 2015	- -
Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	May 07, 2015	- -

Lymphangioma

Pathogenic:1

Pathogenic, no assertion criteria provided

research

James Bennett Lab, Seattle Childrens Research Institute

Feb 09, 2022

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Vascular malformation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Oct 22, 2023

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Carcinoma of colon

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Multiple myeloma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

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

Aug 31, 2019

- -

Nephroblastoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pediatric Oncology, Johns Hopkins University

Feb 15, 2019

- -

Malignant neoplastic disease

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Investigational Cancer Therapeutics, MD Anderson Cancer Center

- -

Cerebral arteriovenous malformation

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

- -

Non-small cell lung carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 29, 2009

- -

Nongerminomatous germ cell tumor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 2014

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2022

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

Thyroid gland undifferentiated (anaplastic) carcinoma

Other:1

-, no assertion criteria provided

clinical testing

National Institute of Cancer Research, National Health Research Institutes

Feb 01, 2024

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). -

Colorectal cancer

Other:1

-, criteria provided, single submitter

curation

CIViC knowledgebase, Washington University School of Medicine

Feb 28, 2019

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. -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Cardio-facio-cutaneous syndrome

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.83

.;.;D;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.65

.;.;N;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.89

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over