rs121913341

Positions:

• chr7-140753350-A-C
• chr7-140753350-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 PP3 PS4_Supporting PM6_Strong PM2 PM1

This summary comes from the ClinGen Evidence Repository: The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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, 16439621). 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). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280058/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 2.30

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 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1905T>G	p.Phe635Leu	missense_variant	16/20	ENST00000644969.2
BRAF	NM_004333.6	c.1785T>G	p.Phe595Leu	missense_variant	15/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1905T>G	p.Phe635Leu	missense_variant	16/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1785T>G	p.Phe595Leu	missense_variant	15/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 28, 2023	This variant is not present in population databases (gnomAD no frequency). 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: 177672). This missense change has been observed in individual(s) with BRAF-related conditions (PMID: 16439621, 29084544, 33040082, 33318624). In at least one individual the variant was observed to be de novo. This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant was identified in multiple registry participants. Variant interpreted as Pathogenic and reported on 05-19-2015 by lab or GTR ID GeneDx. Variant interpreted as Pathogenic and reported on 11-05-2020 by lab or GTR ID Mayo Clinic. GenomeConnect - CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.1785T>G (p.Phe595Leu) variant in BRAF has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 19206169, 18042262; GTR ID's: 26957, 21766; ClinVar SCV000203922.4, SCV000207755.12). The variant has also been identified in at least 2 independent occurences in patients with clinical features of a RASopathy (PS4_Supporting; APHP-Robert Debré internal data; GTR ID 28338). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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, 16439621). 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). Computational prediction tools and conservation analysis suggest that the p.Phe595Leu variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PM2, PM1, PP2, PP3, PS4_Supporting. -

Cardio-facio-cutaneous syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2014	The Phe595Leu variant in BRAF has been reported in the literature in one individ ual with clinical features of Cardio-facio-cutaneous syndrome (CFC; Rodriguez-Vi ciana 2006). This same amino acid change caused by a different DNA change (c.178 5T>A) has also been reported to have occurred de novo in an individual with clin ical features of CFC syndrome (Schulz 2008). In addition, this variant was not i dentified in either parent of a proband (LMM unpublished data). Computational pr ediction tools and conservation analyses suggest that the Phe595Leu variant may impact the protein. In summary, this variant is likely pathogenic, though additi onal studies are required to fully establish its clinical significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2021	Variant summary: BRAF c.1785T>G (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein Kinase Domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes (gnomAD). c.1785T>G has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome (examples: Rodrigues-Viciana_2006, Sarkozy_2009, Yoon_2007, Pierpont_2010, Abe_2012, Alfieri_2013, Lee_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant has been reviewed and classified as pathogenic by the ClinGen RASopathy Expert Panel (Gelb et al., 2018); This variant is associated with the following publications: (PMID: 16439621, 18042262, 12068308, 32269299, 29752777, 33040082, 26582644, 30138938, 24957944, 15488754, 29493581, 15520807, 17603483, 23093928, 30977659, 32913992, 29084544, 19206169) -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Melanoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.9	.;.;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.2	.;.;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	.;.;.;D
Polyphen		1.0	.;.;D;.
MutPred		0.97		Loss of methylation at K591 (P = 0.1346);.;Loss of methylation at K591 (P = 0.1346);.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121913341; hg19: chr7-140453150; COSMIC: COSV56088678;