7-140778006-T-G

Variant names:

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

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>C​(p.Glu501Ala) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 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]

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-G is Pathogenic according to our data. Variant chr7-140778006-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 40373.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>C	p.Glu541Ala	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1502A>C	p.Glu501Ala	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>C	p.Glu541Ala	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1502A>C	p.Glu501Ala	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

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 02, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu501Ala (GAA>GCA): c.1502 A>C in exon 12 of the BRAF gene (NM_004333.4). The E501A missense mutation in the BRAF gene has not been previously reported in association with Cardio-Facio-Cutaneous syndrome. However, the E501 codon appears to be a hot spot for gain-of-function mutations, as other amino acid substitutions altering this codon, E501V, E501G and E501K, have been reported in patients with CFC syndrome (Nava et al., 2007 and Niihori et al., 2006). Functional in vitro studies have demonstrated that the E501G mutation results in decreased kinase activity and activation of downstream effectors (MEK and ERK) (Rodriguez-Viciana et al., 2008). The mechanism by which a presumed gain-of-function mutation would result in lower kinase activity in comparison to the wild-type protein is not clear (Rodriguez-Viciana et al., 2008). The variant is found in NOONAN panel(s). -

Apr 07, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Aug 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome Uncertain:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiofaciocutaneous syndrome 1 Other:1

-

GenomeConnect - CFC International

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 12-05-2016 by Lab or GTR ID Mater Pathology. 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. -

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	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	2.9	.;.;M;.
PrimateAI	Pathogenic	0.91	D
REVEL	Pathogenic	1.0
Polyphen		1.0	.;.;D;.
MutPred		0.98		Gain of MoRF binding (P = 0.0198);.;Gain of MoRF binding (P = 0.0198);.;
MVP		0.99
MPC		2.2
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)		0.0		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: rs180177039; hg19: chr7-140477806;