7-140753392-A-T

Variant names:

• chr7-140753392-A-T
• rs397516895
• NM_001374258.1:c.1863T>A

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_004333.6(BRAF):​c.1743T>A​(p.Asn581Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N581D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense, splice_region
• Scores: Splicing: ADA: 0.7832
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.00

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 19 ACMG points.

• PM1: In a helix (size 2) in uniprot entity BRAF_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004333.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-140754187-T-C is described in Lovd as [Pathogenic].
• 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, 0.979
• PP5: Variant 7-140753392-A-T is Pathogenic according to our data. Variant chr7-140753392-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44811.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.1863T>A	p.Asn621Lys	missense_variant, splice_region_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1743T>A	p.Asn581Lys	missense_variant, splice_region_variant	Exon 15 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1863T>A	p.Asn621Lys	missense_variant, splice_region_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1743T>A	p.Asn581Lys	missense_variant, splice_region_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lung carcinoma;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Mar 24, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asn581Lys variant has been reported in the literature as a de novo variant i n one individual with the clinical features of Cardio-facio-cutaneous syndrome ( Nava 2007). Therefore, this variant is highly likely to be pathogenic. -

not provided Pathogenic:1

Aug 18, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N581K variant has been published previously as apparently de novo in association with cardio-facio-cutaneous (CFC) syndrome (Nava et al., 2007). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). N581K 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 within the protein kinase catalytic loop that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (N581D) and in nearby residues (N580D) have been reported in the Human Gene Mutation Database in association with CFC syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	.;.;M;.
PrimateAI	Pathogenic	0.88	D
REVEL	Pathogenic	0.90
Polyphen		1.0	.;.;D;.
MutPred		0.92		Loss of catalytic residue at N581 (P = 5e-04);.;Loss of catalytic residue at N581 (P = 5e-04);.;
MVP		0.95
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.050		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: rs397516895; hg19: chr7-140453192;