chr7-140801533-A-C

Position:

• chr7-140801533-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP2 PS4_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, 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). 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA135140/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:1
• Conservation: PhyloP100: 9.27

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 Likely_pathogenic. Variant got 7 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.739T>G	p.Phe247Val	missense_variant	6/20	ENST00000644969.2
BRAF	NM_004333.6	c.739T>G	p.Phe247Val	missense_variant	6/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.739T>G	p.Phe247Val	missense_variant	6/20		NM_001374258.1
BRAF	ENST00000646891.2	c.739T>G	p.Phe247Val	missense_variant	6/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Chen2021[review], 24957944, 15488754, 16439621, 15520807, 17603483, 29493581) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

May 10, 2019

The c.739T>G (p.Phe247Val) variant in BRAF has been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx internal data; GTR Lab IDs 21766, 26957; ClinVar SCV000061624.5, SCV000330320.6). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant is located in the BRAF gene, 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). 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). A different pathogenic missense variant (p.Phe247Leu) has been previously identified at this codon of BRAF which may indicate that this residue is critical to the function of the protein (PM5 not usable due to PM1 application; ClinVar 180784, 55793). Computational prediction tools and conservation analysis suggest that the p.Phe247Val variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PM1, PP2, PP3. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2022

ClinVar contains an entry for this variant (Variation ID: 44830). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Phe247 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28512244, 33040082, 33128510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789, 32005694). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the BRAF protein (p.Phe247Val). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 10, 2013

The Phe247Val variant in BRAF has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stron g support for or against an impact to the protein. In summary, additional inform ation is needed to fully asses the clinical significance of the Phe247Val varian t. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;.;D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	.;.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.6	.;.;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Uncertain	0.0080	.;.;.;D
Polyphen		0.29	.;.;B;.
Vest4		0.81
MutPred		0.73		Loss of catalytic residue at F247 (P = 0.1199);Loss of catalytic residue at F247 (P = 0.1199);Loss of catalytic residue at F247 (P = 0.1199);Loss of catalytic residue at F247 (P = 0.1199);
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.97

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: rs397516903; hg19: chr7-140501333;