chr7-140778054-A-G

Variant names:

• chr7-140778054-A-G
• rs397507475
• NM_001374258.1:c.1574T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP3 PP2 PM2 PM5 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). 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). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). 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): PM2, PS4_Moderate, PP2, PP3, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280052/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.29
• Publications: 21 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

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374258.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	NM_001374258.1	MANE Plus Clinical	c.1574T>C	p.Leu525Ser	missense	Exon 13 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.1454T>C	p.Leu485Ser	missense	Exon 12 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.1574T>C	p.Leu525Ser	missense	Exon 13 of 19	NP_001361173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAF	ENST00000644969.2	MANE Plus Clinical	c.1574T>C	p.Leu525Ser	missense	Exon 13 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.1454T>C	p.Leu485Ser	missense	Exon 12 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.1574T>C	p.Leu525Ser	missense	Exon 13 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461078 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726868

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111708

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:2

Oct 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu485Ser variant in BRAF has been reported in 3 individuals with Cardio-fac io-cutaneous syndrome. All of these individuals had severe seizure disorders (Yo on 2007, Aizaki 2011, Adachi, 2012). It was absent from large population studies . In addition, another variant (Leu485Phe) at this position was identified in > 5 individuals with a RASopathy suggesting that changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the Leu485Ser variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, although additional stud ies are required to fully establish its clinical significance, the Leu485Ser var iant is likely pathogenic.

Aug 19, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRAF c.1454T>C (p.Leu485Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR001245) 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 251326 control chromosomes (gnomAD). c.1454T>C has been reported in the literature in individuals affected with Cardio-facio-cutaneous syndrome (Yoon_2007, Aizaki_2011, Adachi_2012); of note, all of these reported individuals had severe seizure disorders. These data indicate that the variant may be associated with disease. Other missense variants affecting this residue (Leu485Phe, Leu485del) has been reported in patients (HGMD and PMID: 30842599), supporting the functional importance of this amino acid. Publications reported experimental evidence and demonstrated that the variant altered gene expression signatures similar to KRAS activation (Berger_2016), and also modified the synaptic signal transduction cascade (Lim_2017). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided Pathogenic:2

Jul 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 16474404, 18039235, 21871821, 18413255, 24803665, 20395089)

Apr 22, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Pathogenic:1

Mar 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Apr 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Pathogenic:1

Feb 27, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1454T>C (p.Leu485Ser) variant in BRAF is absent from gnomAD (PM2). It has been identified in at least 4 patients clinically diagnosed with Cardiofaciocutaneous syndrome (CFC) (PS4_Moderate; 18039235, 21871821, 20395089, SCV000197150.4). 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). Additionally, computational prediction tools and conservation analysis suggest that p.Leu485Ser may affect the protein (PP3). Two different pathogenic missense variants have been previously identified at this codon of BRAF, each resulting in p.Leu485Phe, which supports that this residue may be critical to the function of the protein (PM5; ClinVar 177844, 13975). A functional assay has been performed on this variant, but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:16474404). 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): PM2, PS4_Moderate, PP2, PP3, PM5.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
MutPred		0.90		Gain of disorder (P = 0.0187)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397507475; hg19: chr7-140477854; COSMIC: COSV56173975; COSMIC: COSV56173975;