Menu
GeneBe

rs113488022

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_001374258.1(BRAF):c.1919T>G(p.Val640Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V640A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

BRAF
NM_001374258.1 missense

Scores

6
5
2

Clinical Significance

Pathogenic reviewed by expert panel P:3U:1O:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 10 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 chr7-140753336-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 13961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant where missense usually causes diseases, BRAF
PP3
MetaRNN computational evidence supports a deleterious effect, 0.909
PP5
Variant 7-140753336-A-C is Pathogenic according to our data. Variant chr7-140753336-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 40389.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRAFNM_001374258.1 linkuse as main transcriptc.1919T>G p.Val640Gly missense_variant 16/20 ENST00000644969.2
BRAFNM_004333.6 linkuse as main transcriptc.1799T>G p.Val600Gly missense_variant 15/18 ENST00000646891.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRAFENST00000644969.2 linkuse as main transcriptc.1919T>G p.Val640Gly missense_variant 16/20 NM_001374258.1
BRAFENST00000646891.2 linkuse as main transcriptc.1799T>G p.Val600Gly missense_variant 15/18 NM_004333.6 P4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeAug 30, 2022This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 600 of the BRAF protein (p.Val600Gly). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 40389). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 20735442). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelJun 25, 2020The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. -
Melanoma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
not provided Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Cardio-facio-cutaneous syndrome Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.36
Cadd
Pathogenic
31
Dann
Uncertain
1.0
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Benign
-0.37
T
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.84
D
Polyphen
0.82
.;.;P;.
MutPred
0.75
Loss of stability (P = 0.0081);.;Loss of stability (P = 0.0081);.;
MVP
0.99
MPC
1.8
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.98
gMVP
0.96

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.

Other links and lift over

dbSNP: rs113488022; hg19: chr7-140453136; COSMIC: COSV56080151; API