rs397516905

Variant names:

• chr7-140801479-C-G
• rs397516905
• NM_001374258.1:c.793G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-140801479-C-G
• chr7-140801479-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3 PP2 PM1 PM6 PM2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.793G>C (p.Gly265Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in one proband diagnosed with a RASopathy (PM6, PS4_Supporting; Laboratory for Molecular Medicine internal data, ClinVar SCV000061628.5). 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). Computational prediction tools and conservation analysis suggest that the p.Gly265Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM1, PM2, PM6, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261666/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 7.86
• Publications: 6 publications found

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]

BRAF Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• 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 rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.793G>C	p.Gly265Arg	missense_variant	Exon 6 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.793G>C	p.Gly265Arg	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.793G>C	p.Gly265Arg	missense_variant	Exon 6 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.793G>C	p.Gly265Arg	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: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Mar 14, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PP2 and PP3; This guanine to cytosine change in the BRAF gene at nucleotide position 793 (c.793G>C) leads to the substitution of a glycine for an arginine at amino acid position 265 (p.Gly265Arg) [NC_000007.13:g.140501279C>G, NM_004333.4:c.793G>C (p.Gly265Arg)]. The identified variant was not observed in a large genomic database of reportedly healthy individuals (gnomAD), occurs at a highly conserved amino acid position, is predicted to have deleterious impact on the BRAF protein as determined by multiple in silico algorithms, and is located within a protein domain of BRAF in which other alterations known to be associated with Noonan syndrome related disorders are clustered. This alteration meets ACMG guidelines for classification as a likely pathogenic variant. -

Jul 01, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.793G>C (p.Gly265Arg) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It was observed as a de novo occurrence in one proband diagnosed with a RASopathy (PM6, PS4_Supporting; Laboratory for Molecular Medicine internal data, ClinVar SCV000061628.5). 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). Computational prediction tools and conservation analysis suggest that the p.Gly265Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM1, PM2, PM6, PP2, PP3. -

Noonan syndrome Pathogenic:1 Uncertain:1

Jan 08, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly265Arg variant in BRAF has been identified by our laboratory in 1 indiv idual with Noonan syndrome and occurred de novo. The variant has not been identi fied in large population studies. The glycine (Gly) at position 265 in BRAF is h ighly conserved in mammals and evolutionarily distant species, though additional computational prediction tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to f ully establish its clinical significance, the p.Gly265Arg variant is likely path ogenic. -

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;.;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.4	.;.;M;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.3	.;.;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;.;.;D
Sift4G	Uncertain	0.0050	.;.;.;D
Polyphen		0.97	.;.;D;.
Vest4		0.94
MutPred		0.64		Gain of MoRF binding (P = 0.0438);Gain of MoRF binding (P = 0.0438);Gain of MoRF binding (P = 0.0438);Gain of MoRF binding (P = 0.0438);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.93
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397516905; hg19: chr7-140501279; COSMIC: COSV109420825; COSMIC: COSV109420825;