7-140781605-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001374258.1(BRAF):c.1523T>C(p.Phe508Ser) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F508L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BRAF
NM_001374258.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.30

Publications

40 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 19 ACMG points.

PM1

In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr7-140781606-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1163474.Status of the report is criteria_provided_single_submitter, 1 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, 0.965

PP5

Variant 7-140781605-A-G is Pathogenic according to our data. Variant chr7-140781605-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 40366.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.1523T>C	p.Phe508Ser	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1403T>C	p.Phe468Ser	missense_variant	Exon 11 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.1523T>C	p.Phe508Ser	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2 link	c.1403T>C	p.Phe468Ser	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251424

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000329

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26150740, 23093928, 17551924, 24803665, 31263281, 16439621, 18042262, 24957944, 15488754, 15520807, 17603483) -

Oct 20, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiofaciocutaneous syndrome 1

Pathogenic:1

Feb 19, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes:PS2, PS4M, PM1, PM2, PP2, PP3, PP5 -

See cases

Pathogenic:1

Nov 29, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM1, PM6, PP2, PP3 -

BRAF-related disorder

Pathogenic:1

Feb 24, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRAF c.1403T>C variant is predicted to result in the amino acid substitution p.Phe468Ser. This variant has been reported in at least six individuals with cardio-facio-cutaneous syndrome (Rodriguez-Viciana et al. 2006. PubMed ID: 16439621; Gripp et al. 2007. PubMed ID: 17551924; Nava et al. 2007. PubMed ID: 17704260; Schulz et al. 2007. PubMed ID: 18042262) and one individual with Noonan syndrome (Xu et al. 2017. PubMed ID: 29084544). In at least three individuals this variant occurred de novo (Gripp et al. 2007. PubMed ID: 17551924; Schulz et al. 2007. PubMed ID: 18042262). Additionally, different amino acid substitutions affecting the same (p.Phe468Cys) and adjacent (p.Ser467Ala, p.Gly469Arg, p.Gly469Glu) amino acids have been reported as pathogenic (Human Gene Mutation Database). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-140481405-A-G). This variant is interpreted as pathogenic. -

Cardio-facio-cutaneous syndrome

Pathogenic:1

Jun 02, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Apr 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RASopathy

Pathogenic:1

Dec 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 40366). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 468 of the BRAF protein (p.Phe468Ser). This variant is present in population databases (rs397507473, gnomAD 0.0009%). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome or other RASopathy disorders (PMID: 16439621, 17551924, 18042262, 29084544). In at least one individual the variant was observed to be de novo. 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. 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

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;.;D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.4

.;.;L;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.90

REVEL

Pathogenic

0.88

Polyphen

0.47

.;.;P;.

MutPred

0.91

Gain of disorder (P = 0.003);.;Gain of disorder (P = 0.003);.;

MVP

1.0

MPC

2.4

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.94

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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