chr7-140801536-C-G

Variant names:

• chr7-140801536-C-G
• rs180177034
• NM_001374258.1:c.736G>C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM6 PM2 PP2 PP3 PS3 PS2

This summary comes from the ClinGen Evidence Repository: The c.736G>C (p.Ala246Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262). In vitro functional studies provide some evidence that the p.Ala246Pro variant may impact protein function (PS3; 16474404, 19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.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). This variant is in a location which 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.Ala246Pro variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PM6, PS2, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA279968/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 7.86

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 16 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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 rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.736G>C	p.Ala246Pro	missense_variant	Exon 6 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.736G>C	p.Ala246Pro	missense_variant	Exon 6 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.736G>C	p.Ala246Pro	missense_variant	Exon 6 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.736G>C	p.Ala246Pro	missense_variant	Exon 6 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 1 Pathogenic:2

-

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Molecular Genetics, Centre for Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Jan 11, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16474404, 19376813).In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.84 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013965 /PMID: 16474404).The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16474404, 18042262). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardio-facio-cutaneous syndrome Pathogenic:2

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.736G>C (p.Ala246Pro) variant in BRAF has been reported in the literature as a de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6 and PS2; PMID 16474404 and 18042262). In vitro functional studies provide some evidence that the p.Ala246Pro variant may impact protein function (PS3; 16474404, 19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.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). This variant is in a location which 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.Ala246Pro variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PM6, PS2, PS3. -

Jan 23, 2015

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jun 09, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM1, PM2, PM6, PS2, PS3, PS4 -

Apr 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect that the A246P variant results in increased ELK-dependent transcription, leading to activation of BRAF and stimulation of downstream effectors (MEK and ERK) (Niihori et al., 2006); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19376813, 24409384, 34573299, 30141192, 20523244, 16474404, 18042262, 23885229, 24803665, 28809097, 28911804, 27666661, 31560489, 35418823, 24957944, 15488754, 16439621, 15520807, 17603483, 29493581, 17704260) -

Noonan syndrome 7 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.736G>C (p.Ala246Pro) variant in BRAF gene has been reported in heterozygous state in individuals affected with cardio-facio-cutaneous syndrome or Noonan syndrome (Ohtake A et al., 2011). Experimental studies have shown that this missense increased ELK-dependent transcription, leading to activation of BRAF and stimulation of downstream effectors (MEK and ERK) (Niihori et al., 2006). The p.Ala246Pro variant is novel (not in any individuals) in gnomAD and in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Ala at position 246 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala246Pro in BRAF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

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

Aug 02, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala246Pro variant in BRAF has been reported in 6 individuals with clinical features of Cardio-facio-cutaneous syndrome (CFC) (Niihori 2006, Nava 2007, Nys trom 2008, Schulz 2008, Ohtake 2011). This variant occurred de novo in 2 of thes e individuals (Niihori 2006, Schulz 2008), and one of these individuals also had Non-Hodgkin Lymphoma (Ohtake 2011). Furthermore, this variant has now been iden tified by our laboratory in 5 individuals with clinical features of Noonan syndr ome and/or CFC syndrome. It was also absent from large population studies. There fore, this variant meets our criteria to be classified as pathogenic (http://www .partners.org/personalizedmedicine/LMM). -

Noonan syndrome Pathogenic:1

Jun 15, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Jul 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 246 of the BRAF protein (p.Ala246Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cardio-facio-cutaneous syndrome or Noonan syndrome (PMID: 16474404, 20523244, 28911804). ClinVar contains an entry for this variant (Variation ID: 13965). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 16474404). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	.;.;M;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.4	.;.;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	.;.;.;D
Sift4G	Uncertain	0.0050	.;.;.;D
Polyphen		1.0	.;.;D;.
Vest4		0.94
MutPred		0.90		Loss of catalytic residue at A246 (P = 0.0079);Loss of catalytic residue at A246 (P = 0.0079);Loss of catalytic residue at A246 (P = 0.0079);Loss of catalytic residue at A246 (P = 0.0079);
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs180177034; hg19: chr7-140501336;