7-140781603-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001374258.1(BRAF):c.1525G>A(p.Gly509Arg) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.89

Publications

177 publications found

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 Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
cardiofaciocutaneous syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
LEOPARD syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Noonan syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
Noonan syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Noonan syndrome with multiple lentigines
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
anaplastic astrocytoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BRAF links:

ENSG00000289788 (HGNC:):

ENSG00000289788 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 27 ACMG points.

PS1

Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr7-140781602-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13974.Status of the report is reviewed_by_expert_panel, 3 stars.

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: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 7-140781603-C-T is Pathogenic according to our data. Variant chr7-140781603-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 177775.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.1525G>A	p.Gly509Arg	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1405G>A	p.Gly469Arg	missense_variant	Exon 11 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.1525G>A	p.Gly509Arg	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 link	c.1405G>A	p.Gly469Arg	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727182

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60392

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:1

Oct 10, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Jul 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

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

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;.;H;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.94

REVEL

Pathogenic

0.95

Polyphen

1.0

.;.;D;.

MutPred

0.92

Gain of MoRF binding (P = 0.0064);.;Gain of MoRF binding (P = 0.0064);.;

MVP

0.99

MPC

2.2

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.95

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over