chr7-140753346-G-C

Position:

• chr7-140753346-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004333.6(BRAF):​c.1789C>G​(p.Leu597Val) variant causes a missense change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 4.96

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 17 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-140753346-G-C is Pathogenic according to our data. Variant chr7-140753346-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140753346-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1909C>G	p.Leu637Val	missense_variant	16/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1789C>G	p.Leu597Val	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.1909C>G	p.Leu637Val	missense_variant	16/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2	c.1789C>G	p.Leu597Val	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:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2017	The L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L597V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the L597V variant leads to increased protein activity (Sarkozy et al., 2009; Andreadi et al., 2012). Missense variants in nearby residues (F595L, G596V, T599R, V600G, K601Q, K601I, K601T) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L597V as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -

Noonan syndrome 7 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.1909C>G;p.(Leu637Val) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13969; PMID: 19206169) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19206169) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PK_Tyr_Ser-Thr) - PM1. This variant is not present in population databases:rs121913369, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169) PM6. In summary, the currently available evidence indicates that the variant is Pathogenic -

Cardio-facio-cutaneous syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2022	Variant summary: BRAF c.1789C>G (p.Leu597Val) results in a 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. c.1789C>G has been reported in the literature as a de-novo variant in multiple individuals affected with Noonan/Cardiofaciocutaneous syndrome (example, Sarkozy_2009, Pierpont_2010, Stevenson_2011, Timeus_2013, Wei_2021). These data indicate that the variant is likely to be associated with disease. Ras/MAPK dysregulation in development has been deonstrated to cause a skeletal myopathy in an activating Braf-L597V mouse model for cardio-facio-cutaneous syndrome (Maeda_2021). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

Non-small cell lung carcinoma Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 21, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2003	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2016

The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one de novo occurrence (Sarkozy 2009, LMM data). It has not been identifi ed in large population studies. The p.Leu597Val has also been previously reporte d as a somatic mutation in melanomas and non-small cell lung carcinomas (NSCLC)( COSMIC). In vitro functional studies suggest that the p.Leu597Val variant may i mpact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009). In summary, this variant meets the criteria to be classified as pathogenic for Noonan spectrum d isorders in an autosomal dominant manner based upon the de novo occurrence, stat istically significant increase of the allele frequency in affected individuals o ver the general population, and supporting functional evidence. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 03, 2022

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 597 of the BRAF protein (p.Leu597Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13969). 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Noonan syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.5	.;.;L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	D
REVEL	Pathogenic	0.80
Polyphen		0.93	.;.;P;.
MutPred		0.95		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);.;
MVP		0.99
MPC		1.6
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.93
gMVP		0.88

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: rs121913369; hg19: chr7-140453146; COSMIC: COSV56128388;