rs180177039

Variant names:

• chr7-140778006-T-A
• rs180177039
• NM_001374258.1:c.1622A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-140778006-T-A
• chr7-140778006-T-C
• chr7-140778006-T-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_004333.6(BRAF):​c.1502A>T​(p.Glu501Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.98

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]

ENSG00000289788 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity BRAF_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BRAF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 139 curated pathogenic missense variants (we use a threshold of 10). The gene has 21 curated benign missense variants. Gene score misZ: 3.7208 (above the threshold of 3.09). Trascript score misZ: 4.9447 (above the threshold of 3.09). GenCC associations: The gene is linked to LEOPARD syndrome 3, anaplastic astrocytoma, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-140778006-T-A is Pathogenic according to our data. Variant chr7-140778006-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1622A>T	p.Glu541Val	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1502A>T	p.Glu501Val	missense_variant	Exon 12 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1622A>T	p.Glu541Val	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1502A>T	p.Glu501Val	missense_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:2

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (VCV000040374.2, PMID: 17704260, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Glu501Lys, p.Glu501Gly, p.Glu501Ala) at the same codon has been reported as pathogenic (ClinVar ID: VCV000013977.4, VCV000013978.7, VCV000040373.5, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.995, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Sep 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu501Val variant in BRAF has been reported in three individuals with clinic al features of Cardio-facio-cutaneous syndrome (Yoon 2007, Nava 2007, LMM unpubl ished data). It was also absent from large population studies. Different disease -causing amino acid changes (Glu501Lys, Glu501Gly) at this location have been id entified in >10 affected individuals and both of these variants were reported to have occurred de novo in two individuals (Razzaque 2007,Narumi 2007, Niihori 20 06, Rodriguez-Viciana 2006,Rodriguez-Viciana 2008, LMM unpublished data) suggest ing that changes at this position are not tolerated. Additionally, computational prediction tools and evolutionary conservation analysis suggest that the Glu501 Val variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the Glu501Val variant is likely pa thogenic, though additional studies are required to fully establish its clinical significance. -

not provided Pathogenic:1

May 18, 2022

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; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 18039235, 30094826, 33040082, 17704260) -

RASopathy Pathogenic:1

Jul 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu501 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 40374). This variant has been observed in individuals with cardiofaciocutaneous syndrome (PMID: 18039235, 30094826). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with valine at codon 501 of the BRAF protein (p.Glu501Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.2	.;.;M;.
PrimateAI	Pathogenic	0.91	D
REVEL	Pathogenic	0.99
Polyphen		1.0	.;.;D;.
MutPred		0.98		Gain of MoRF binding (P = 0.016);.;Gain of MoRF binding (P = 0.016);.;
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs180177039; hg19: chr7-140477806;