chr7-140778059-T-G

Variant names:

• chr7-140778059-T-G
• rs727504375
• NM_001374258.1:c.1569A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001374258.1(BRAF):​c.1569A>C​(p.Lys523Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K523Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.710
• Publications: 3 publications found

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]

BRAF Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr7-140778061-T-G is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 40369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: 4.9008 (above the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome 1, Noonan syndrome 7, LEOPARD syndrome 3, anaplastic astrocytoma, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 7-140778059-T-G is Pathogenic according to our data. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878. Variant chr7-140778059-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 177878.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.1569A>C	p.Lys523Asn	missense_variant	Exon 13 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1449A>C	p.Lys483Asn	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.1569A>C	p.Lys523Asn	missense_variant	Exon 13 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1449A>C	p.Lys483Asn	missense_variant	Exon 12 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000535 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Feb 15, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

RASopathy Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 483 of the BRAF protein (p.Lys483Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 34643321). ClinVar contains an entry for this variant (Variation ID: 177878). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRAF protein function with a positive predictive value of 80%. This variant disrupts the p.Lys483 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;D;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;.;M;.
PhyloP100		0.71
PrimateAI	Pathogenic	0.91	D
REVEL	Pathogenic	0.87
Polyphen		1.0	.;.;D;.
MutPred		0.76		Loss of ubiquitination at K483 (P = 0.0183);.;Loss of ubiquitination at K483 (P = 0.0183);.;
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504375; hg19: chr7-140477859;