7-140781603-C-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_004333.6(BRAF):​c.1405G>C​(p.Gly469Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

BRAF
NM_004333.6 missense

Scores

13
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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;
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, 0.981
PP5
Variant 7-140781603-C-G is Pathogenic according to our data. Variant chr7-140781603-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13970.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
BRAFNM_001374258.1 linkc.1525G>C p.Gly509Arg missense_variant Exon 12 of 20 ENST00000644969.2 NP_001361187.1
BRAFNM_004333.6 linkc.1405G>C p.Gly469Arg missense_variant Exon 11 of 18 ENST00000646891.2 NP_004324.2 P15056

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRAFENST00000644969.2 linkc.1525G>C p.Gly509Arg missense_variant Exon 12 of 20 NM_001374258.1 ENSP00000496776.1 A0A2R8Y8E0
BRAFENST00000646891.2 linkc.1405G>C p.Gly469Arg missense_variant Exon 11 of 18 NM_004333.6 ENSP00000493543.1 P15056

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461752
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727182
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardio-facio-cutaneous syndrome Pathogenic:1
Oct 17, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRAF c.1405G>C (p.Gly469Arg) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.1405G>C has been widely reported in the literature as a somatic variant in a variety of cancers such as melanoma and in at-least one case of fetal autopsy findings of Cardiofaciocutaneous Syndrome (example, Terry_2014). In the fetal case, both parents denied having personal or family histories of genetic disorders, malformations, or other significant abnormalities. Therefore, although a de-novo etiology is likely, it was not unequivocally established by parental analysis as reported in this study. Furthermore, pathogenic/likely pathogenic variants in HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, SOS1, and exon 2 of SHOC2 were reportedly not identified. At least one publication reports experimental evidence evaluating an impact on protein function (Damm_2014). The most pronounced variant effect results in constitutive ERK phosphorylation and Egr2 transcription along with a decrease in the proprtion of B cells in BRAF-G469R mice, as compared with empty murine stem cell virus vector or BRAF-wild type mice. No clinical diagnostic laboratories have submitted germline clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1
Dec 17, 2012
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The G469R missense mutation has not been reported as a germline mutation to our knowlege; however, a different mutation at this residue (G469E) has been described in patients with Cardio-Facio-Cutaneous (CFC) Syndrome (Niihori et al., 2006). The G469R mutation identified in the fetus has been reported previously as a somatic mutation in association with haematopoietic and lymphoid cancer (Catalogue of Somatic Mutations in Cancer). The G469R missense change is a non-conservative substitution with a neutral, non-polar Gly residue being replaced by a positively-charged Arg residue. The NHLBI ESP Exome Variant Server reports that G469R was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). -

Non-Hodgkin lymphoma Pathogenic:1
Nov 17, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
.;.;D;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.73
D
MutationAssessor
Pathogenic
4.1
.;.;H;.
PrimateAI
Pathogenic
0.94
D
REVEL
Pathogenic
0.95
Polyphen
1.0
.;.;D;.
MutPred
0.92
Gain of MoRF binding (P = 0.0064);.;Gain of MoRF binding (P = 0.0064);.;
MVP
0.99
MPC
2.2
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.95

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.

Other links and lift over

dbSNP: rs121913357; hg19: chr7-140481403; COSMIC: COSV56082352; API