chr7-140781612-C-T

Variant names:

• chr7-140781612-C-T
• rs121913353
• NM_001374258.1:c.1516G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001374258.1(BRAF):​c.1516G>A​(p.Gly506Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G506E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRAF NM_001374258.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.89
• Publications: 107 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 23 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 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr7-140781611-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376073.
• 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, 0.989
• PP5: Variant 7-140781612-C-T is Pathogenic according to our data. Variant chr7-140781612-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44801.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.1516G>A	p.Gly506Arg	missense_variant	Exon 12 of 20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6	c.1396G>A	p.Gly466Arg	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.1516G>A	p.Gly506Arg	missense_variant	Exon 12 of 20		NM_001374258.1	ENSP00000496776.1
BRAF	ENST00000646891.2	c.1396G>A	p.Gly466Arg	missense_variant	Exon 11 of 18		NM_004333.6	ENSP00000493543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461804 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

⚠️ 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: 33476

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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: 53400

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), 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

not provided Pathogenic:1

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRAF c.1396G>A; p.Gly466Arg variant (rs121913353, ClinVar Variation ID: 44801) is reported in the literature in an individual with clinical features of a Rasopathy disorder (Lee 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.963). Additionally, another variant leading to the same amino acid change (c.1396G>C; p.Gly466Arg) has been reported de novo in a fetus with features of cardiofaciocutaneous syndrome and was considered disease-causing (Biard 2019). Functional analysis of the p.Gly466Arg variant, also published as G465R, demonstrates association with increased Erk phosphorylation compared to wildtype BRAF (Houben 2004). Based on available information, the c.1396G>A; p.Gly466Arg variant is considered to be pathogenic. References: Biard JM et al. Antenatal diagnosis of cardio-facio-cutaneous syndrome: Prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. About a case and review of literature. Eur J Obstet Gynecol Reprod Biol. 2019 Sep;240:232-241. PMID: 31336229. Houben R et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004 Mar 26;3:6. PMID: 15046639. Lee Y et al. Clinical and molecular spectra of BRAF-associated RASopathy. J Hum Genet. 2021 Apr;66(4):389-399. PMID: 33040082. -

Non-small cell lung carcinoma Pathogenic:1

Aug 20, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly466Arg variant has been previously reported in the literature in two mela nomas (due to a different nucleotide change, 1396G>C, Kumar 2003, Houben 2004). In one of these tumors, a second variant in NRAS was observed . Different amino acid changes at this position have also been reported (Gly466Val, Gly466Ala, Gl y466Glu, COSMIC). -

Vascular malformation Pathogenic:1

Mar 08, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A BRAF c.1396G>A (p.Gly466Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in the ClinVar database as likely pathogenic in the somatic state by one submitter (ClinVar Variation ID: 44801). This variant resides within a P-loop, amino acids 459-474, of BRAF that is defined as a critical functional domain (Gelb BD et al., PMID: 29493581). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to BRAF function. In support of this prediction, functional studies demonstrate that cells overexpressing BRAF with the p.Gly466Arg variant displayed increased Erk phosphorylation (Houben R et al., PMID: 15046639) and that this variant is inactivating (Ng PK et al., PMID: 29533785). The BRAF gene is defined by the ClinGen's RASopathy expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). The same amino acid change (p.Gly466Arg), resulting from a different nucleotide change, c.1396G>C, has been reported and is considered pathogenic (ClinVar Variation ID: 2501901). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the BRAF c.1396G>A (p.Gly466Arg) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	.;.;H;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
REVEL	Pathogenic	0.96
Polyphen		1.0	.;.;D;.
MutPred		0.94		Gain of MoRF binding (P = 0.0065);.;Gain of MoRF binding (P = 0.0065);.;
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.94
Mutation Taster		=3/97	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: rs121913353; hg19: chr7-140481412; COSMIC: COSV56099462;