chr7-140777032-A-G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001374258.1(BRAF):c.1694T>C(p.Leu565Pro) 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. 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. L565Q) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
BRAF
NM_001374258.1 missense
NM_001374258.1 missense
Scores
9
4
3
Clinical Significance
Conservation
PhyloP100: 9.29
Publications
22 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 syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- cardiofaciocutaneous syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
- LEOPARD syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
- Noonan syndrome 7Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
- Noonan syndromeInheritance: AD Classification: MODERATE Submitted by: ClinGen
- Noonan syndrome with multiple lentiginesInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
- anaplastic astrocytomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 19 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, 6 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 chr7-140777032-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520890.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, 0.979
PP5
Variant 7-140777032-A-G is Pathogenic according to our data. Variant chr7-140777032-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 222077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRAF | ENST00000644969.2 | c.1694T>C | p.Leu565Pro | missense_variant | Exon 14 of 20 | NM_001374258.1 | ENSP00000496776.1 | |||
| BRAF | ENST00000646891.2 | c.1574T>C | p.Leu525Pro | missense_variant | Exon 13 of 18 | NM_004333.6 | ENSP00000493543.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Jul 22, 2015
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Feb 13, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 23093928, 26150740, 33482860, 34573299, 34643321, 19206169, 17551924, 24458522, 29493581, 35595280) -
Apr 05, 2018
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Noonan syndrome 7 Pathogenic:1
Oct 25, 2021
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PM5_STR, PS4_MOD, PM1, PM2_SUP, PP3 -
Melanoma Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research
PS2, PM5, PS4,PM2, PP3 -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;L;.
PhyloP100
PrimateAI
Pathogenic
D
REVEL
Pathogenic
Polyphen
0.98
.;.;D;.
MutPred
Gain of disorder (P = 0.0695);.;Gain of disorder (P = 0.0695);.;
MVP
0.99
MPC
2.6
ClinPred
D
GERP RS
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
Publications
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