rs121913376

Positions:

• chr7-140781597-C-A
• chr7-140781597-C-G
• chr7-140781597-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS3 PM6 PM2 PS4_Supporting PP3 PP2 PM1

This summary comes from the ClinGen Evidence Repository: The c.1411G>T (p.Val471Phe) variant in BRAF was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in at least 2 individuals diagnosed with RASopathies (PS4_Supporting; PMID:22495831, 30937965). One of these cases was shown to be a de novo occurrence without maternity or paternity confirmed (PM6). In vitro functional studies provide some evidence that the p.Val471Phe variant may impact protein function (PS3; PMID:25348715). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581). Computational prediction tools and conservation analysis suggest that the p.Val471Phe variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA281968/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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]

BRAF (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1531G>T	p.Val511Phe	missense_variant	12/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1411G>T	p.Val471Phe	missense_variant	11/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1531G>T	p.Val511Phe	missense_variant	12/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1411G>T	p.Val471Phe	missense_variant	11/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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 17, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 24803665, 25348715, 15488754, 15520807, 16439621, 17603483, 24957944, 29493581, 31475041, 22495831) -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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
DEOGEN2	Pathogenic	0.97	.;.;D;.
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
MutationAssessor	Pathogenic	3.1	.;.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.2	.;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;.;.;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;