7-140801550-G-T

Position:

• chr7-140801550-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4_Supporting PM6_Strong PP3 PP2 PM2 PM1

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_004333.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.94

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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.722C>A	p.Thr241Lys	missense_variant	6/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.722C>A	p.Thr241Lys	missense_variant	6/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.722C>A	p.Thr241Lys	missense_variant	6/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.722C>A	p.Thr241Lys	missense_variant	6/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 29, 2022	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 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). 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). -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Jun 25, 2020	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. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 07, 2013

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 v4.3

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;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;.;M;.
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);Gain of methylation at T241 (P = 0.0078);Gain of methylation at T241 (P = 0.0078);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906660; hg19: chr7-140501350;