7-140778061-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.1567A>C(p.Lys523Gln) 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. K523E) 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:2 O:1
• Conservation: PhyloP100: 7.99

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, 5 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 chr7-140778060-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1198003.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, BRAF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 7-140778061-T-G is Pathogenic according to our data. Variant chr7-140778061-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1567A>C	p.Lys523Gln	missense_variant	13/20	ENST00000644969.2
BRAF	NM_004333.6	c.1447A>C	p.Lys483Gln	missense_variant	12/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1567A>C	p.Lys523Gln	missense_variant	13/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1447A>C	p.Lys483Gln	missense_variant	12/18		NM_004333.6	P4
	ENST00000700122.1	n.502+3193T>G		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:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 02, 2014	The Lys483Gln variant in BRAF has been identified in one proband with clinical f eatures of Cardio-facio-cutaneous syndrome, and was not identified in either of this individual's parents (LMM unpublished data). This variant has not been iden tified in large population studies. In addition, another variant at the same res idue (Lys483Asn) was identified as a de novo variant in an individual with featu res of a Noonan spectrum disorder (LMM unpublished data). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) suggest that the Lys483Gln variant may impact the normal function of the prot ein. In summary, this variant is likely pathogenic, though additional studies ar e required to fully establish its clinical significance. -
not provided, no classification provided	phenotyping only	GenomeConnect - CFC International	-	Variant interpreted as Likely pathogenic and reported on 04-02-2014 by lab or GTR ID 21766. 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. Phenotypic details are available under supporting information. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2023

Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Located within protein kinase domain;ATP binding site (PMID: 19624854); This variant is associated with the following publications: (PMID: 26918529, 19624854, 33839364, 34625582, 29696744) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Polyphen		1.0	.;.;D;.
MutPred		0.78		Loss of ubiquitination at K483 (P = 0.0183);.;Loss of ubiquitination at K483 (P = 0.0183);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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: rs397507474; hg19: chr7-140477861;