rs397516893

Positions:

• chr7-140778048-A-C
• chr7-140778048-A-T

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.1460T>G​(p.Val487Gly) 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: 9.29

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 (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 gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.942
• PP5: Variant 7-140778048-A-C is Pathogenic according to our data. Variant chr7-140778048-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140778048-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1580T>G	p.Val527Gly	missense_variant	13/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1460T>G	p.Val487Gly	missense_variant	12/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1580T>G	p.Val527Gly	missense_variant	13/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1460T>G	p.Val487Gly	missense_variant	12/18		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

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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: 26795593, 17366577, 24719372, 18470943, 18413255, 33482860, 24803665) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 21, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2015

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2012

The Val487Gly variant in BRAF has been identified in one individual with Cardio- Facio-Cutaneous (CFC) syndrome and was absent in 210 Caucasian control chromosom es (Narumi 2007). Valine (Val) at position 487 is highly conserved across evolut ionarily distant species, increasing the likelihood that the change would not be tolerated. Computational analyses (biochemical amino acid properties, conservat ion, AlignGVGD, PolyPhen2 and SIFT) suggest that the Val487Gly variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, this variant is likely to be pathogenic, though segregat ion studies and functional analyses are required to fully establish the pathogen icity of this variant. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2021

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 44806). This variant has been observed in individuals with BRAF-related conditions (PMID: 17366577, 22495831, 24719372, 26795593). This sequence change replaces valine with glycine at codon 487 of the BRAF protein (p.Val487Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	.;.;L;.
PrimateAI	Pathogenic	0.83	D
REVEL	Pathogenic	0.87
Polyphen		0.48	.;.;P;.
MutPred		0.83		Gain of disorder (P = 0.0281);.;Gain of disorder (P = 0.0281);.;
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516893; hg19: chr7-140477848;