7-140754206-G-T

Position:

• chr7-140754206-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001374258.1(BRAF):​c.1842C>A​(p.His614Gln) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H614Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.39

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 15 ACMG points.

• PS1: Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 40384
• PM1: In a hotspot region, there are 4 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 chr7-140754208-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 44810.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 4.9008 (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, 0.983
• PP5: Variant 7-140754206-G-T is Pathogenic according to our data. Variant chr7-140754206-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 180788.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAF	NM_001374258.1	c.1842C>A	p.His614Gln	missense_variant	15/20	ENST00000644969.2
BRAF	NM_004333.6	c.1722C>A	p.His574Gln	missense_variant	14/18	ENST00000646891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAF	ENST00000644969.2	c.1842C>A	p.His614Gln	missense_variant	15/20		NM_001374258.1
BRAF	ENST00000646891.2	c.1722C>A	p.His574Gln	missense_variant	14/18		NM_004333.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2014

p.His574Gln (CAC>CAA): c.1722 C>A in exon 14 of the BRAF gene (NM_004333.4). It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H574Q missense mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H574Q mutation is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (D565G, D565E, N580D, N581D) have been reported in association with BRAF-related disorders, supporting the functional importance of this region of the protein. Therefore, H574Q is interpreted as a disease-causing mutation. The variant is found in NOONAN panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	4.0	.;.;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
REVEL	Pathogenic	0.95
Polyphen		1.0	.;.;D;.
MutPred		0.97		Gain of methylation at K570 (P = 0.0851);.;Gain of methylation at K570 (P = 0.0851);.;
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.99

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: rs397507481; hg19: chr7-140454006; COSMIC: COSV56187605;