rs113488022

Positions:

• chr7-140753336-A-C
• chr7-140753336-A-G
• chr7-140753336-A-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID:20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID:20735442). 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; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the 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 RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA281998/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1 O:1
• Conservation: PhyloP100: 9.24

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]

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.1919T>G	p.Val640Gly	missense_variant	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1799T>G	p.Val600Gly	missense_variant	15/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1919T>G	p.Val640Gly	missense_variant	16/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1799T>G	p.Val600Gly	missense_variant	15/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2022	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 600 of the BRAF protein (p.Val600Gly). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 40389). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 20735442). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Jun 25, 2020	The c.1799T>G (p.Val600Gly) variant in BRAF is absent from gnomAD (PM2). It has been identified in one individual with Cardiofaciocutaneous syndrome (PS4_Supporting; PMID: 20735442). It has also been reported in the literature as an unconfirmed de novo occurrence (PM6; GeneDx internal communication). In vitro functional studies provide some evidence that the p.Val600Gly variant may impact protein function (PS3; PMID: 20735442). 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; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Val600Gly variant may impact the protein (PP3). Finally, the 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 RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS3, PM1, PM2, PM6, PS4_Supporting, PP3, PP2. -

Melanoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Cardio-facio-cutaneous syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.5	.;.;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
REVEL	Pathogenic	0.93
Polyphen		0.82	.;.;P;.
MutPred		0.75		Loss of stability (P = 0.0081);.;Loss of stability (P = 0.0081);.;
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.96

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: rs113488022; hg19: chr7-140453136; COSMIC: COSV56080151;