rs121913376

chr7-140781597-C-Achr7-140781597-C-Gchr7-140781597-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):c.1531G>T(p.Val511Phe) 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. V511I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr7-140781597-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40368.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 7-140781597-C-A is Pathogenic according to our data. Variant chr7-140781597-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1531G>T	p.Val511Phe	missense_variant	12/20	ENST00000644969.2
BRAF	NM_004333.6	c.1411G>T	p.Val471Phe	missense_variant	11/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1531G>T	p.Val511Phe	missense_variant	12/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1411G>T	p.Val471Phe	missense_variant	11/18		NM_004333.6	P4
	ENST00000700122.1	n.502+6729C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 25, 2022

The c.1411G>T;p.(Val471Phe) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40367; PMID: 22495831 )PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Pkinase_Tyr) - PM1. This variant is not present in population databases (rs121913376- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 40368) - PM5. Missense variant in BRAF that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. In summary, the currently available evidence indicates that the variant is pathogenic -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2012

TheV471F missense mutation in the BRAF gene hasbeen reported previously in association with cardio-facio-cutaneous syndrome (CFC) (Abe et al., 2012). The V471F amino acid substitution is conservative as a both Valine and Phenylalanine residues are neutral and non-polar. The position at which this substitution occurs is highly conserved and many other missense mutations (S467A, F468S, G469E, L485F, L485S) have been reported in nearby codons in association with cardio-facio-cutaneous syndrome (CFC) (Rodriguez-Viciana et al., 2006; Niihori et al., 2006; Rodriguez-Viciana et al., 2008; Aoki et al., 2008). The variant is found in NOONAN panel(s). -

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

May 21, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects BRAF protein function (PMID: 25348715). 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. This variant has been observed in individual(s) affected with cardio-facio-cutaneous (CFC) syndrome and RASopathy spectrum disorders (PMID: 22495831, 31475041, Invitae). ClinVar contains an entry for this variant (Variation ID: 40367). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 471 of the BRAF protein (p.Val471Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	31
Dann	Uncertain	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	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	.;.;D;.
MutPred		0.93		Loss of MoRF binding (P = 0.0797);.;Loss of MoRF binding (P = 0.0797);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
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

Other links and lift over

dbSNP: rs121913376; hg19: chr7-140481397; COSMIC: COSV56229839;