7-140781603-C-G

Variant names:

• chr7-140781603-C-G
• rs121913357
• NM_001374258.1:c.1525G>C

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):​c.1525G>C​(p.Gly509Arg) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G509E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.89
• Publications: 177 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 syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• LEOPARD syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Noonan syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet
• anaplastic astrocytoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000289788 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 27 ACMG points.

• PS1: Transcript NM_001374258.1 (BRAF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr7-140781602-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13974.Status of the report is reviewed_by_expert_panel, 3 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, 0.981
• PP5: Variant 7-140781603-C-G is Pathogenic according to our data. Variant chr7-140781603-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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
BRAF	NM_001374258.1	c.1525G>C	p.Gly509Arg	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1405G>C	p.Gly469Arg	missense_variant	Exon 11 of 18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2	c.1525G>C	p.Gly509Arg	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1405G>C	p.Gly469Arg	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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;.
PhyloP100		7.9
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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