NM_004333.6(BRAF):c.722C>T (p.Thr241Met) AND Noonan syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 2, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000211753.6

Allele description [Variation Report for NM_004333.6(BRAF):c.722C>T (p.Thr241Met)]

NM_004333.6(BRAF):c.722C>T (p.Thr241Met)

Gene:

BRAF:B-Raf proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_004333.6(BRAF):c.722C>T (p.Thr241Met)

Other names:

p.T241M:ACG>ATG; NM_004333.4(BRAF):c.722C>T(p.Thr241Met)

HGVS:

NC_000007.14:g.140801550G>A
NG_007873.3:g.128215C>T
NM_001354609.2:c.722C>T
NM_001374244.1:c.722C>T
NM_001374258.1:c.722C>T
NM_001378467.1:c.731C>T
NM_001378468.1:c.722C>T
NM_001378469.1:c.722C>T
NM_001378470.1:c.620C>T
NM_001378471.1:c.722C>T
NM_001378472.1:c.566C>T
NM_001378473.1:c.566C>T
NM_001378474.1:c.722C>T
NM_001378475.1:c.458C>T
NM_004333.6:c.722C>TMANE SELECT
NP_001341538.1:p.Thr241Met
NP_001361173.1:p.Thr241Met
NP_001361187.1:p.Thr241Met
NP_001365396.1:p.Thr244Met
NP_001365397.1:p.Thr241Met
NP_001365398.1:p.Thr241Met
NP_001365399.1:p.Thr207Met
NP_001365400.1:p.Thr241Met
NP_001365401.1:p.Thr189Met
NP_001365402.1:p.Thr189Met
NP_001365403.1:p.Thr241Met
NP_001365404.1:p.Thr153Met
NP_004324.2:p.Thr241Met
LRG_299t1:c.722C>T
LRG_299:g.128215C>T
NC_000007.13:g.140501350G>A
NM_001354609.1:c.722C>T
NM_004333.4:c.722C>T
NM_004333.5:c.722C>T
P15056:p.Thr241Met
c.722C>T

Protein change:

T153M; THR241MET

Links:

UniProtKB: P15056#VAR_058620; OMIM: 164757.0022; dbSNP: rs387906660

NCBI 1000 Genomes Browser:

rs387906660

Molecular consequence:

NM_001354609.2:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.731C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.620C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.566C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.566C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.458C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061620	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Nov 2, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19206169, 24803665, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061620

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Nov 2, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum.

Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, Scioletti AP, Esposito G, Cordeddu V, Lepri F, Petrangeli V, Dentici ML, Mancini GM, Selicorni A, Rossi C, Mazzanti L, Marino B, Ferrero GB, Silengo MC, Memo L, Stanzial F, Faravelli F, et al.

Hum Mutat. 2009 Apr;30(4):695-702. doi: 10.1002/humu.20955.

PubMed [citation]

PMID:: 19206169
PMCID:: PMC4028130

Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.

Kiel C, Serrano L.

Mol Syst Biol. 2014 May 6;10:727. doi: 10.1002/msb.20145092.

PubMed [citation]

PMID:: 24803665
PMCID:: PMC4188041

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061620.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

Last Updated: Oct 8, 2024

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