rs387906660

Positions:

Variant summary

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

The NM_004333.6(BRAF):c.722C>T(p.Thr241Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRAF
NM_004333.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 9.94

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]

BRAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a zinc_finger_region Phorbol-ester/DAG-type (size 46) in uniprot entity BRAF_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_004333.6

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRAF. . Gene score misZ 3.7208 (greater than the threshold 3.09). Trascript score misZ 4.9447 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.973

PP5

Variant 7-140801550-G-A is Pathogenic according to our data. Variant chr7-140801550-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-140801550-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAF	NM_001374258.1 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	6/20	ENST00000644969.2	NP_001361187.1
BRAF	NM_004333.6 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	6/18	ENST00000646891.2	NP_004324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAF	ENST00000644969.2 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	6/20		NM_001374258.1	ENSP00000496776
BRAF	ENST00000646891.2 linkuse as main transcript	c.722C>T	p.Thr241Met	missense_variant	6/18		NM_004333.6	ENSP00000493543	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726420

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30414707, 19206169, 24803665, 28991257, 30525188, 32369273, 15488754, 16439621, 17603483, 24957944, 15520807, 29493581, 32368696, 33644862, 33040082, 33004838) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	BRAF: PS2, PM5, PM2:Supporting, PP2, PP3, PS4:Supporting -

Noonan syndrome 7

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jan 29, 2021	The heterozygousc.722C>T (p.Thr241Met) variant identified in the BRAF gene has been reported in multiple individuals affected with Noonan, LEOPARD, and Cardio-facio-cutaneous syndromes (PMID: 19206169,32369273). The p.Thr241Met variant has also been reported in anindividual affected with moderate intellectual disability and generalized epilepsy (PMID:30525188). This variant has been reported as heterozygous in one out of 152,100 individuals in the gnomAD(v3) database suggesting it is extremely rare in the populations represented in gnomAD. The variant affects an evolutionary conserved residue and is predicted deleterious by multiple in silico prediction tools. The variant is reported in the ClinVar database as pathogenic/likely pathogenic by multiple independent laboratories (ClinVarID: 29805). A different missense variant affecting the same residue Thr241 has also been reported in individuals affected with Cardio-facio-cutaneous syndrome suggesting that p.Thr241is important for the normalprotein function. Based on the available evidence, the heterozygousc.722C>T (p.Thr241Met) variant identified in the BRAF gene is reported here as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 07, 2021	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2, PS4, PM5_STR, PM1, PM2_SUP, PP2, PP3 -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Noonan syndrome 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:19206169). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. -

Noonan syndrome 1

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.722C>T;p.(Thr241Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 29805; PMID: 19206169; 33040082; 30414707; 29522538; https://doi.org/10.1016/j.annonc.2021.08.1975) - PS4.The variant is located in a mutational hot spot and/or critical and well-established functional domain (C1_1 domain) - PM1. This variant is not present in population databases (rs387906660, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 29806; 29807; 44829) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169; 30414707) - PM6. Missense variant in BRAF that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	-	- -

Lung carcinoma;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Cardiofaciocutaneous syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in one patient with Noonan syndrome [PMID 19206169] Muscle weakness and peripheral neuropathy have been reported in individuals with CFC1 [PMID 16007634, 17437909, 22907230] -

Cardio-facio-cutaneous syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 24, 2023

Variant summary: BRAF c.722C>T (p.Thr241Met) results in a non-conservative amino acid change located in the Protein kinase C-like, phorbol ester/diacylglycerol-binding domain (IPR002219) 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 248524 control chromosomes (gnomAD). c.722C>T has been reported in the literature in multiple individuals affected with Cardiofaciocutaneous Syndrome, Noonan Syndrome and Congenital heart disease (examples: Sarkozy_2009, Jin_2017, Okuzono_2019, Edwards_2020, Lee_2021, and Hiraide_2021) and multiple cases are reported as de novo occurrences (examples: Jin_2017, Okuzono_2019, Edwards_2020, and Hiraide_2021). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

BRAF-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2023

The BRAF c.722C>T variant is predicted to result in the amino acid substitution p.Thr241Met. This variant was reported in numerous individuals with BRAF-associated disorders, including at least four de novo cases (Okuzono et al. 2019. PubMed ID: 30414707; supplementary database 2, Edwards et al. 2020. PubMed ID: 32368696; Table S1, Kosaki et al. 2020. PubMed ID: 32369273; Hiraide et al. 2021. PubMed ID: 33644862; Swarts et al. 2022. PubMed ID: 35979676). This variant is reported in 0.00079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-140501350-G-A). This variant is interpreted as pathogenic. -

Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 02, 2017

The p.Thr241Met variant in BRAF has been previously reported in 3 individuals wi th clinical features of Noonan syndrome, including 2 de novo occurrences (LMM da ta, Sarkozy 2009, ClinVar Variation ID 29805). It has also been identified in 1/ 124756 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org; dbSNP rs387906660). Furthermore, 3 other missense vari ants at position p.241 (p.Thr241Arg, p.Thr241Pro, p.Thr241Lys) have been identif ied in individuals with clinical features of Noonan syndrome, Cardio-facio-cutan eous syndrome, LEOPARD, or Costello syndrome (Sarkozy 2009, LMM data), suggestin g that changes at this position are not tolerated. In summary, the p.Thr241Met v ariant meets criteria to be classified as pathogenic for Noonan syndrome in an a utosomal dominant manner. ACMG/AMP Criteria applied: PM5_Strong; PM6_Strong; PM2 ; PP2. -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr241 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 18042262, 23950000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. ClinVar contains an entry for this variant (Variation ID: 29805). This missense change has been observed in individual(s) with Noonan Syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 241 of the BRAF protein (p.Thr241Met). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;.;D;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

.;.;M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.6

.;.;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;.;.;D

Sift4G

Pathogenic

0.0010

.;.;.;D

Polyphen

1.0

.;.;D;.

Vest4

0.88

MutPred

0.89

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.97

MPC

2.0

ClinPred

1.0

GERP RS

5.2

Varity_R

0.86

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over