7-140778006-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_004333.6(BRAF):c.1502A>G(p.Glu501Gly) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.98

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:

ENSG00000289788 (HGNC:):

ENSG00000289788 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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, 0.99

PP5

Variant 7-140778006-T-C is Pathogenic according to our data. Variant chr7-140778006-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1 link	c.1622A>G	p.Glu541Gly	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1502A>G	p.Glu501Gly	missense_variant	Exon 12 of 18	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.1622A>G	p.Glu541Gly	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 link	c.1502A>G	p.Glu501Gly	missense_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cardiofaciocutaneous syndrome 1

Pathogenic:2Other:1

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 1647440, 17366577, 17704260, PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu501Lys and pGlu501Ala) has been reported as pathogenic (VCV000013977.4, VCV000040373.5, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.992, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Jul 23, 2015

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 16439621, 18413255, 17366577, 16474404, 24803665, 32959227, 30732632, 30141192, 30094826, 17704260, 17483702) -

Ventricular septal defect;C0151526:Premature birth;C0221217:Webbed neck;C0239676:High forehead;C0340279:Ventricular hypertrophy;C0423110:Downslanted palpebral fissures;C1827524:Wide intermamillary distance;C1857486:Low-set, posteriorly rotated ears;C1956257:Pulmonic stenosis;C4281993:Neonatal respiratory distress

Pathogenic:1

Oct 08, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome

Pathogenic:1

Nov 21, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu501Gly variant has been reported in at least 7 individuals with clinical features of Cardio-facio-cutaneous syndrome and was absent from 280 control chro mosomes (Niihori 2006, Rodriguez-Viciana 2006, Narumi 2007, Rodriguez-Viciana 20 08). In addition, this variant was reported to have occurred de novo in two indi viduals, supporting a pathogenic role. Furthermore, glutamic acid (Glu) at posi tion 501 is highly conserved across evolutionarily distant species into C. elega ns and computational analyses (AlignGVGD, PolyPhen2, SIFT) predict that a change to a glycine (Gly) at this position may impact the protein. Based on this info rmation, this variant is highly likely to be pathogenic. The presence of a heter ozygous pathogenic variant in BRAF is consistent with a diagnosis of Cardio-faci o-cutaneous syndrome but this information should be reconciled with the complete clinical history of this individual. -

Familial cardiofaciocutaneous syndrome

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy

Pathogenic:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 501 of the BRAF protein (p.Glu501Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16439621, 16474404, 17483702). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13978). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt BRAF function with a negative predictive value of 95%. This variant disrupts the p.Glu501 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169, 20186801, 25463315). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;D;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.2

.;.;M;.

PrimateAI

Pathogenic

0.90

REVEL

Pathogenic

0.99

Polyphen

1.0

.;.;D;.

MutPred

0.99

Gain of MoRF binding (P = 0.0235);.;Gain of MoRF binding (P = 0.0235);.;

MVP

0.99

MPC

2.3

ClinPred

1.0

GERP RS

5.0

Varity_R

0.95

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

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