NM_004333.6(BRAF):c.735A>C (p.Leu245Phe) AND Cardio-facio-cutaneous syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 28, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000037956.6

Allele description [Variation Report for NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)]

NM_004333.6(BRAF):c.735A>C (p.Leu245Phe)

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.735A>C (p.Leu245Phe)

Other names:

p.L245F:TTA>TTC; NM_004333.4(BRAF):c.735A>C

HGVS:

NC_000007.14:g.140801537T>G
NG_007873.3:g.128228A>C
NM_001354609.2:c.735A>C
NM_001374244.1:c.735A>C
NM_001374258.1:c.735A>C
NM_001378467.1:c.744A>C
NM_001378468.1:c.735A>C
NM_001378469.1:c.735A>C
NM_001378470.1:c.633A>C
NM_001378471.1:c.735A>C
NM_001378472.1:c.579A>C
NM_001378473.1:c.579A>C
NM_001378474.1:c.735A>C
NM_001378475.1:c.471A>C
NM_004333.6:c.735A>CMANE SELECT
NP_001341538.1:p.Leu245Phe
NP_001361173.1:p.Leu245Phe
NP_001361187.1:p.Leu245Phe
NP_001365396.1:p.Leu248Phe
NP_001365397.1:p.Leu245Phe
NP_001365398.1:p.Leu245Phe
NP_001365399.1:p.Leu211Phe
NP_001365400.1:p.Leu245Phe
NP_001365401.1:p.Leu193Phe
NP_001365402.1:p.Leu193Phe
NP_001365403.1:p.Leu245Phe
NP_001365404.1:p.Leu157Phe
NP_004324.2:p.Leu245Phe
LRG_299t1:c.735A>C
LRG_299:g.128228A>C
NC_000007.13:g.140501337T>G
NM_004333.4:c.735A>C
P15056:p.Leu245Phe
c.735A>C

Protein change:

L157F; LEU245PHE

Links:

UniProtKB: P15056#VAR_058623; OMIM: 164757.0027; dbSNP: rs397507466

NCBI 1000 Genomes Browser:

rs397507466

Molecular consequence:

NM_001354609.2:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374244.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001374258.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378467.1:c.744A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378468.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378469.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378470.1:c.633A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378471.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378472.1:c.579A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378473.1:c.579A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378474.1:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001378475.1:c.471A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004333.6:c.735A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Cardio-facio-cutaneous syndrome
Synonyms:: Cardiofaciocutaneous syndrome; CFC syndrome
Identifiers:: MONDO: MONDO:0015280; MedGen: C1275081; Orphanet: 1340; OMIM: PS115150

Recent activity

Clear Turn Off Turn On

filaggrin-2 [Homo sapiens]
filaggrin-2 [Homo sapiens]
gi|62122917|ref|NP_001014364.1|

Protein
RecName: Full=Hornerin
RecName: Full=Hornerin
gi|45476906|sp|Q86YZ3.2|HORN_HUMAN

Protein

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061622	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jun 24, 2010)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19416762, 19206169, 24033266
SCV001467792	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 28, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19416762, 31560489, 30581057, 30290804 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061622

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jun 24, 2010)

germline

clinical testing

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

SCV001467792

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 28, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061622.5

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

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001467792.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: BRAF c.735A>C (p.Leu245Phe) results in a non-conservative amino acid change located in the 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 250260 control chromosomes (gnomAD). c.735A>C has been reported in the literature as a de novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome and related phenotypes belonging to the RASopathy spectrum (Koudova_2009, Pekeles_2019, Chinton_2019). In addition, a different variant resulting in the same missense change (c.735A>T (p.Leu245Phe)) has been reported in affected individuals (HGMD). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (3x, including the expert panel) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine