7-140753332-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_004333.6(BRAF):c.1803A>C(p.Lys601Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K601I) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-140753333-T-A 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAF	NM_001374258.1 link	c.1923A>C	p.Lys641Asn	missense_variant	Exon 16 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 link	c.1803A>C	p.Lys601Asn	missense_variant	Exon 15 of 18	ENST00000646891.2	NP_004324.2	P15056

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 link	c.1923A>C	p.Lys641Asn	missense_variant	Exon 16 of 20		NM_001374258.1	ENSP00000496776.1		A0A2R8Y8E0
BRAF	ENST00000646891.2 link	c.1803A>C	p.Lys601Asn	missense_variant	Exon 15 of 18		NM_004333.6	ENSP00000493543.1		P15056

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726696

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RASopathy

Uncertain:1

Mar 31, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine with asparagine at codon 601 of the BRAF protein (p.Lys601Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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. This variant disrupts the p.Lys601 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19206169, 22495831,28832562, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 376286). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;.

Eigen

Benign

0.099

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.2

.;.;L;.

PrimateAI

Pathogenic

0.88

REVEL

Pathogenic

0.65

Polyphen

0.92

.;.;P;.

MutPred

0.72

Loss of ubiquitination at K601 (P = 0.0183);.;Loss of ubiquitination at K601 (P = 0.0183);.;

MVP

0.86

MPC

1.2

ClinPred

0.99

GERP RS

4.5

Varity_R

0.98

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over