rs397516904

Positions:

Variant summary

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

The NM_004333.6(BRAF):c.785A>G(p.Gln262Arg) 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. Q262P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.97

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:

BRAF (HGNC:):

BRAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a zinc_finger_region Phorbol-ester/DAG-type (size 46) in uniprot entity BRAF_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004333.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-140801487-T-G is described in Lovd as [Likely_pathogenic].

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, 0.932

PP5

Variant 7-140801487-T-C is Pathogenic according to our data. Variant chr7-140801487-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.785A>G	p.Gln262Arg	missense_variant	6/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.785A>G	p.Gln262Arg	missense_variant	6/18	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.785A>G	p.Gln262Arg	missense_variant	6/20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 linkuse as main transcript	c.785A>G	p.Gln262Arg	missense_variant	6/18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727168

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 17, 2023	Multiple missense variants at this residue [p.(Q262K) and p.(Q262P)] have been reported in association with BRAF-related RASopathy in patients previously tested at GeneDx and in the published literature (Ciara et al., 2015; Schulz et al., 2008); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24957944, 15488754, 16439621, 15520807, 17603483, 29493581, 24803665, 17704260, 19953625, 29907801, 30050098, 32185055, 25463315, 18042262) -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2024

The c.785A>G (p.Q262R) alteration is located in exon 6 (coding exon 6) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 785, causing the glutamine (Q) at amino acid position 262 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with BRAF-related RASopathy (Nava, 2007; Denayer, 2010; Leach, 2019; Dell'Edera, 2020). Two other alterations at the same codon, c.785A>C (p.Q262P) and c.784C>A (p.Q262K), have been detected in patients with cardiofaciocutaneous syndrome (Schulz, 2008; Ciara, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

RASopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2015

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Likely Pathogenic. Two other missense substitutions at this codon (p.Gln262Lys and p.Gln262Pro) have been reported as de novo mutations in patients affected with cardio-facio-cutaenous syndrome (PMID: 18042262, 25463315). This suggests that the glutamine residue is important for BRAF protein function. This variant was reported in an individual affected with cardio-facio-cutaneous syndrome (PMID: 17704260) and in an individual affected with Noonan syndrome (PMID: 19953625). Full parental testing was not performed in either cases, but were suspected to be sporadic. This variant is not present in population databases and has been reported in the literature. ClinVar also contains an entry for this variant (RCV000157699). This sequence change replaces glutamine with arginine at codon 262 of the BRAF protein (p.Gln262Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

.;.;D;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.085

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.031

MutationAssessor

Benign

0.68

.;.;N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.4

.;.;.;N

REVEL

Pathogenic

0.71

Sift

Benign

0.25

.;.;.;T

Sift4G

Benign

0.25

.;.;.;T

Polyphen

0.48

.;.;P;.

Vest4

0.90

MutPred

0.88

Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);

MVP

0.99

MPC

1.6

ClinPred

0.93

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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