rs397507469

Positions:

• chr7-140801503-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_004333.6(BRAF):​c.769C>A​(p.Gln257Lys) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q257R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAF NM_004333.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.72

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a zinc_finger_region Phorbol-ester/DAG-type (size 46) in uniprot entity BRAF_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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 chr7-140801502-T-C is described in Lovd as [Pathogenic].
• 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 4.9447 (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, 0.91
• PP5: Variant 7-140801503-G-T is Pathogenic according to our data. Variant chr7-140801503-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801503-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1	c.769C>A	p.Gln257Lys	missense_variant	6/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.769C>A	p.Gln257Lys	missense_variant	6/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.769C>A	p.Gln257Lys	missense_variant	6/20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.769C>A	p.Gln257Lys	missense_variant	6/18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 02, 2015

The p.Gln257Lys variant in BRAF has been reported in 2 individuals with clinical features of Cardio-facio-cutaneous syndrome (CFC, Narumi 2007, LMM unpublished data) and was absent from large population studies. In addition, another variant at this position (p.Gln257Arg) has been identified in >20 individuals with a RA Sopathy, suggesting that changes at this position are not tolerated. Computation al prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln257Lys variant is likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 07, 2013

p.Gln257Lys (CAG>AAG): c.769 C>A in exon 6 of the BRAF gene (NM_004333.4). The Q257K mutation in the BRAF gene has been reported previously in association with Cardio-Facio- Cutaneous (CFC) Syndrome (Narumi et al., 2007; Aoki et al., 2008). The codon at which this missense mutation occurs is a hot spot" where the most common recurrent mutation in CFC identified thus far (Q257R) occurs. The variant is found in NOONAN panel(s)." -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2023

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 257 of the BRAF protein (p.Gln257Lys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gln257 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474404, 17703371, 24719372, 24775816). 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function. ClinVar contains an entry for this variant (Variation ID: 40351). This missense change has been observed in individuals with cardio-facio-cutaneous syndrome (CFC) (PMID: 17366577, 33040082). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;.;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	.;.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	.;.;.;N
REVEL	Pathogenic	0.71
Sift	Benign	0.038	.;.;.;D
Sift4G	Benign	0.33	.;.;.;T
Polyphen		0.48	.;.;P;.
Vest4		0.77
MutPred		0.90		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.99
MPC		1.2
ClinPred		0.85	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.99

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: rs397507469; hg19: chr7-140501303; COSMIC: COSV56081983; COSMIC: COSV56081983;