rs397507469
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001374258.1(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_001374258.1 missense
NM_001374258.1 missense
Scores
6
5
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 chr7-140801502-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13973.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
?
Missense variant where missense usually causes diseases, BRAF
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 | UniProt |
---|---|---|---|---|---|---|---|
BRAF | NM_001374258.1 | c.769C>A | p.Gln257Lys | missense_variant | 6/20 | ENST00000644969.2 | |
BRAF | NM_004333.6 | c.769C>A | p.Gln257Lys | missense_variant | 6/18 | ENST00000646891.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.769C>A | p.Gln257Lys | missense_variant | 6/20 | NM_001374258.1 | |||
BRAF | ENST00000646891.2 | c.769C>A | p.Gln257Lys | missense_variant | 6/18 | NM_004333.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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 | Invitae | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
Polyphen
0.48
.;.;P;.
Vest4
0.77
MutPred
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
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at