chr7-140801550-G-T

Variant names:

• chr7-140801550-G-T
• rs387906660
• NM_001374258.1:c.722C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3 PP2 PM1 PM2 PS4_Supporting PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.722C>A (p.Thr241Lys) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in 1 individual with Noonan syndrome and 1 individual with cardiofaciocutaneous syndrome (PS4_Supporting; Otto von Guericke University Magdeburg internal data, Laboratory for Molecular Medicine internal data; ClinVar SCV000061619.5). It has been reported at least twice as a de novo occurrence without confirmation of maternity or paternity (PM6_Strong; Fulgent Genetics, Laboratory for Molecular Medicine internal data, SCV000061619.5). 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; 29493581). In addition, 3 other pathogenic or likely pathogenic variants have been identified at this codon (PM5 not applied; ClinVar ID: 29805, 29806, 29807). Computational prediction tools and conservation analysis suggest that the p.Thr241Lys variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM6_Strong, PM1, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261663/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.94
• Publications: 37 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: Pathogenic. The variant received 11 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.

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.722C>A	p.Thr241Lys	missense	Exon 6 of 20	NP_001361187.1
	BRAF	NM_004333.6	MANE Select	c.722C>A	p.Thr241Lys	missense	Exon 6 of 18	NP_004324.2
	BRAF	NM_001374244.1		c.722C>A	p.Thr241Lys	missense	Exon 6 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.722C>A	p.Thr241Lys	missense	Exon 6 of 20	ENSP00000496776.1
	BRAF	ENST00000646891.2	MANE Select	c.722C>A	p.Thr241Lys	missense	Exon 6 of 18	ENSP00000493543.1
	BRAF	ENST00000288602.11	TSL:1	c.722C>A	p.Thr241Lys	missense	Exon 6 of 19	ENSP00000288602.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Jun 25, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.722C>A (p.Thr241Lys) variant in BRAF was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in 1 individual with Noonan syndrome and 1 individual with cardiofaciocutaneous syndrome (PS4_Supporting; Otto von Guericke University Magdeburg internal data, Laboratory for Molecular Medicine internal data; ClinVar SCV000061619.5). It has been reported at least twice as a de novo occurrence without confirmation of maternity or paternity (PM6_Strong; Fulgent Genetics, Laboratory for Molecular Medicine internal data, SCV000061619.5). 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; 29493581). In addition, 3 other pathogenic or likely pathogenic variants have been identified at this codon (PM5 not applied; ClinVar ID: 29805, 29806, 29807). Computational prediction tools and conservation analysis suggest that the p.Thr241Lys variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS4_Supporting, PM6_Strong, PM1, PM2, PP2, PP3.

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change has been observed in individual(s) with clinical features of RASopathy spectrum disorders (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 241 of the BRAF protein (p.Thr241Lys). This variant disrupts the p.Thr241 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 18042262, 19206169, 28404629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 44829).

Noonan syndrome Pathogenic:1

Jun 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr241Lys variant has not been reported in the literature nor been identifie d in our laboratory in over 1,400 individuals. However, two nucleotide variants at this same position (722C>T, Thr241Met; 722C>G, Thr241Arg) have been previousl y reported in two patients with Noonan syndrome (Sarkozy 2009), one of which was shown to have occurred de novo. Moreover, an adjacent variant affecting the sam e amino acid codon (721A>C, Thr241Pro) has been identified in four patients with Cardio-facio-cutaneous syndrome or LEOPARD syndrome (Nava 2007, Schulz 2008, Sa rkozy 2009), with three of these patients having had the variant occur de novo. In addition, this variant was not identified in the parents of this proband. The se data suggest the threonine (Thr) at position 241, and residing within the con served region 1 (CR1) of BRAF, is a functionally important residue and is strong ly associated with Noonan Spectrum disorders. In summary, given the de novo occu rrence, the Thr241Lys variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.83		Gain of methylation at T241 (P = 0.0078)
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.97
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs387906660; hg19: chr7-140501350;