7-140781618-C-T

Position:

• chr7-140781618-C-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):​c.1510G>A​(p.Gly504Arg) 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. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G504E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.89

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 23 ACMG points.

• PS1: Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 279992
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr7-140781617-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13964.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 7-140781618-C-T is Pathogenic according to our data. Variant chr7-140781618-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140781618-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1510G>A	p.Gly504Arg	missense_variant	12/20	ENST00000644969.2
BRAF	NM_004333.6	c.1390G>A	p.Gly464Arg	missense_variant	11/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1510G>A	p.Gly504Arg	missense_variant	12/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1390G>A	p.Gly464Arg	missense_variant	11/18		NM_004333.6	P4
	ENST00000700122.1	n.502+6750C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 24, 2015

While the nucleotide substitution c.1390 G>A in the BRAF gene has not been reported previously, another nucleotide substitution at the same position, c.1390 G>C, has been published in association with Cardio-Facio-Cutaneous (CFC) Syndrome (Cave et al., 2008). Both nucleotide changes result in a non-conservative amino acid substitution of a highly conserved neutral, non-polar Glycine with a positively charged Arginine, designated G464R. The NHLBI ESP Exome Variant Server reports G464R was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Additionally, in silico algorithms predict that G464R is not tolerated. Although this mutation has not been reported previously to our knowledge, its presence is consistent with a diagnosis of a Noonan spectrum disorder -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 464 of the BRAF protein (p.Gly464Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with BRAF-related syndromes (PMID: 17704260; Invitae). ClinVar contains an entry for this variant (Variation ID: 372572). 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 with a positive predictive value of 80%. This variant disrupts the p.Gly464 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18039235, 18413255, 19376813, 23907581). 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. -

Prostate cancer, hereditary, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca

Jul 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Polyphen		1.0	.;.;D;.
MutPred		0.98		Gain of MoRF binding (P = 0.0264);.;Gain of MoRF binding (P = 0.0264);.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.89

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

Other links and lift over

dbSNP: rs121913349; hg19: chr7-140481418; COSMIC: COSV56250103;