Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase 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 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1783T>C (p.Phe595Leu)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1783T>C (p.Phe595Leu)
Variation ID: 202193 Accession: VCV000202193.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 140753352 (GRCh38) [ NCBI UCSC ] 7: 140453152 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 3, 2015 Feb 14, 2024 Dec 9, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1783T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Phe595Leu missense NM_001374258.1:c.1903T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Phe635Leu missense NM_001354609.2:c.1783T>C NP_001341538.1:p.Phe595Leu missense NM_001374244.1:c.1903T>C NP_001361173.1:p.Phe635Leu missense NM_001378467.1:c.1792T>C NP_001365396.1:p.Phe598Leu missense NM_001378468.1:c.1783T>C NP_001365397.1:p.Phe595Leu missense NM_001378469.1:c.1717T>C NP_001365398.1:p.Phe573Leu missense NM_001378470.1:c.1681T>C NP_001365399.1:p.Phe561Leu missense NM_001378471.1:c.1672T>C NP_001365400.1:p.Phe558Leu missense NM_001378472.1:c.1627T>C NP_001365401.1:p.Phe543Leu missense NM_001378473.1:c.1627T>C NP_001365402.1:p.Phe543Leu missense NM_001378474.1:c.1783T>C NP_001365403.1:p.Phe595Leu missense NM_001378475.1:c.1519T>C NP_001365404.1:p.Phe507Leu missense NC_000007.14:g.140753352A>G NC_000007.13:g.140453152A>G NG_007873.3:g.176413T>C LRG_299:g.176413T>C LRG_299t1:c.1783T>C P15056:p.Phe595Leu - Protein change
- F595L, F573L, F598L, F543L, F561L, F635L, F507L, F558L
- Other names
- -
- Canonical SPDI
- NC_000007.14:140753351:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1250 | 1364 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
|
Nov 1, 2016 | RCV000184039.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 11, 2023 | RCV000414439.5 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000427091.1 | |
| Uncertain significance (1) |
no assertion criteria provided
|
Jul 29, 2022 | RCV002291588.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 31, 2022 | RCV002222430.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 9, 2023 | RCV002516942.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781087.1
First in ClinVar: Jul 03, 2015 Last updated: Jul 03, 2015 |
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500808.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five … (more)
Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase 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 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491004.3
First in ClinVar: Jan 09, 2017 Last updated: Aug 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581) (less)
|
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003516832.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 06, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: yes
Allele origin:
unknown
|
Mendelics
Accession: SCV000236570.1
First in ClinVar: Jul 03, 2015 Last updated: Jul 03, 2015 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000505590.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Uncertain significance
(Jul 29, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Prostate cancer, hereditary, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca
Accession: SCV002584889.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Age: 49-92 years
Sex: male
Ethnicity/Population group: Moroccan
Geographic origin: Morocco
|
Comment:
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581)
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Variant summary: BRAF c.1783T>C (p.Phe595Leu) results in a non-conservative amino acid change located in the Protein kinase 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 251240 control chromosomes (gnomAD). c.1783T>C has been reported in the literature in individuals affected with Cardiofaciocutaneous Syndrome (Ciara_2015, Matalon_2021), and in one case the de novo occurrence of the variant was confirmed. In addition two equivalent missense variants (c.1785T>A (p.F595L) and c.1785T>G (p.F595L)) have also been reported in patients affected with Cardio-facio-cutaneous syndrome (HGMD). These data indicate that the variant is likely associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in low to intermediate Braf kinase activity, which works cooperatively with Ras leading to increased MEK/ERK signaling (Kordes_2016, Yao_2017, Ng_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the germline state to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F594L); This variant is associated with the following publications: (PMID: 22142829, 24803665, 37039257, 33683002, 28856074, 34573299, 31060855, 32913992, 18039235, MelchorL2015[Abstract], 31573083, 33128510, 29533785, 19206169, 20186801, 18042262, 21871821, 22495831, 29084544, 23093928, 35226061, 33198372, 34331515, 36448195, 26826419, 37530550, 26582644, 16439621, 15035987, 25463315, 24957944, 15488754, 15520807, 17603483, 29493581)
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 595 of the BRAF protein (p.Phe595Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 18042262, 19206169, 20186801, 21871821, 22495831, 23093928, 25463315, 29084544). In at least one individual the variant was observed to be de novo. This variant is also known as F594L. ClinVar contains an entry for this variant (Variation ID: 202193). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BRAF function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRAF function (PMID: 26582644). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cardiofaciocutaneous Syndrome. | Adam MP | - | 2023 | PMID: 20301365 |
| Congenital polyvalvular disease expands the cardiac phenotype of the RASopathies. | Matalon DR | American journal of medical genetics. Part A | 2021 | PMID: 33683002 |
| Systematic Functional Annotation of Somatic Mutations in Cancer. | Ng PK | Cancer cell | 2018 | PMID: 29533785 |
| Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders. | Xu S | BMC medical genomics | 2017 | PMID: 29084544 |
| Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling. | Kordes M | Leukemia | 2016 | PMID: 26582644 |
| Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF1 gene. | Ciara E | European journal of medical genetics | 2015 | PMID: 25463315 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. | Cheng TM | PLoS computational biology | 2012 | PMID: 23093928 |
| Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey. | Abe Y | American journal of medical genetics. Part A | 2012 | PMID: 22495831 |
| Epilepsy in RAS/MAPK syndrome: two cases of cardio-facio-cutaneous syndrome with epileptic encephalopathy and a literature review. | Adachi M | Seizure | 2012 | PMID: 21871821 |
| Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. | Pierpont EI | American journal of medical genetics. Part A | 2010 | PMID: 20186801 |
| Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
| Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
| Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
| Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
| http://docm.genome.wustl.edu/variants/ENST00000288602:c.1783T>C | - | - | - | - |
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Text-mined citations for rs794729219 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.