rs180177037

chr7-140778013-T-Cchr7-140778013-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):c.1615A>G(p.Lys539Glu) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K539Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001374258.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140778011-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 7-140778013-T-C is Pathogenic according to our data. Variant chr7-140778013-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140778013-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1615A>G	p.Lys539Glu	missense_variant	13/20	ENST00000644969.2
BRAF	NM_004333.6	c.1495A>G	p.Lys499Glu	missense_variant	12/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1615A>G	p.Lys539Glu	missense_variant	13/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1495A>G	p.Lys499Glu	missense_variant	12/18		NM_004333.6	P4
	ENST00000700122.1	n.502+3145T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 1 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Nov 22, 2021	PM1, PM2, PM5, PP2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	Amino acid change identical t o known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000013976, PMID:16474404). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000040371,VCV000040372, PMID:18042262). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported. In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.829>=0.6). A missense variant is a common mechanism associated with Cardiofaciocutaneous syndrome. It is absent from the gnomAD v2.1.1 dataset. ATherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant interpreted as Pathogenic and reported on 02-12-2018 by Lab or GTR ID Kaizer Franz Josef Hospital. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	The K499E missense variant in the BRAF gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome (Niihori et al., 2006; Schulz et al., 2008). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). K499E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional in vitro studies demonstrate that K499E results in increased kinase activity (Rodriguez-Viciana et al., 2008). Additionally, missense variants in the same (K499N) and a nearby residue (E501K/G/V/A) have been reported in the Human Gene Mutation Database in association with cardio-facio-cutaneous syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, K499E is interpreted as a pathogenic variant. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 09, 2018

Variant summary: BRAF c.1495A>G (p.Lys499Glu) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246384 control chromosomes (in gnomAD and publication data). c.1495A>G has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008). These data indicate that the variant may be associated with disease. Two publications report experimental evidence evaluating an impact on protein function, and both of them demonstrated an increased kinase activity for the variant protein (Rodriguez-Viciana 2006, Niihori 2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	-0.034
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.90	D
Polyphen		0.049	.;.;B;.
MutPred		0.91		Loss of MoRF binding (P = 0.0164);.;Loss of MoRF binding (P = 0.0164);.;
MVP		0.99
MPC		2.1
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.86

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: rs180177037; hg19: chr7-140477813; COSMIC: COSV56065660; COSMIC: COSV56065660;