ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004333.6(BRAF):c.1781A>T (p.Asp594Val)
Variation ID: 375946 Accession: VCV000375946.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140753354 (GRCh38) [ NCBI UCSC ] 7: 140453154 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 8, 2017 Feb 20, 2024 May 18, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6(BRAF):c.1781A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
missense NM_004333.6:c.1781A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Asp594Val missense NM_001374258.1:c.1901A>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Asp634Val missense NM_001354609.2:c.1781A>T NP_001341538.1:p.Asp594Val missense NM_001374244.1:c.1901A>T NP_001361173.1:p.Asp634Val missense NM_001378467.1:c.1790A>T NP_001365396.1:p.Asp597Val missense NM_001378468.1:c.1781A>T NP_001365397.1:p.Asp594Val missense NM_001378469.1:c.1715A>T NP_001365398.1:p.Asp572Val missense NM_001378470.1:c.1679A>T NP_001365399.1:p.Asp560Val missense NM_001378471.1:c.1670A>T NP_001365400.1:p.Asp557Val missense NM_001378472.1:c.1625A>T NP_001365401.1:p.Asp542Val missense NM_001378473.1:c.1625A>T NP_001365402.1:p.Asp542Val missense NM_001378474.1:c.1781A>T NP_001365403.1:p.Asp594Val missense NM_001378475.1:c.1517A>T NP_001365404.1:p.Asp506Val missense NC_000007.14:g.140753354T>A NC_000007.13:g.140453154T>A NG_007873.3:g.176411A>T LRG_299:g.176411A>T LRG_299t1:c.1781A>T - Protein change
- D594V, D506V, D542V, D557V, D560V, D572V, D597V, D634V
- Other names
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- Canonical SPDI
- NC_000007.14:140753353:T:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1224 | 1333 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2014 | RCV000421094.1 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000434803.1 | |
Pathogenic (2) |
reviewed by expert panel
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May 18, 2020 | RCV000796335.7 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000824925.1 |
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
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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
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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. |
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Pathogenic
(May 18, 2020)
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reviewed by expert panel
Method: curation
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RASopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV001424741.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
Comment:
The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical … (more)
The c.1781A>T (p.Asp594Val) variant in BRAF was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The variant has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000935844.1, SCV000965957.1, GeneDx internal data). In one proband, the variant was reported as de novo with confirmed parentage (PS2). The c.1781A>T (p.Asp594Val) variant is located in the CR3 activation segment of BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the variant may impact protein function (PP3). Finally, c.1781A>T (p.Asp594Val) is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Moderate, PM1, PM2, PP2, PP3, (less)
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Uncertain significance
(Dec 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000935844.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been reported to affect BRAF protein function (PMID: 18413255, 20141835, 19376813, 19735675). This variant has been observed in an individual affected with cardio-facio-cutaneous syndrome (PMID: 18413255). ClinVar contains an entry for this variant (Variation ID: 375946). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 594 of the BRAF protein (p.Asp594Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. (less)
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Pathogenic
(Oct 02, 2014)
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no assertion criteria provided
Method: literature only
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Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504289.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504290.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Cardio-facio-cutaneous syndrome
Affected status: yes
Allele origin:
unknown
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Service de Génétique Moléculaire, Hôpital Robert Debré
Accession: SCV000965957.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Number of individuals with the variant: 1
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
The road to resistance: EGFR mutation and cetuximab. | Bardelli A | Nature medicine | 2012 | PMID: 22310681 |
Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy? | Rizzo S | Cancer treatment reviews | 2010 | PMID: 21129611 |
Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. | Tejpar S | The oncologist | 2010 | PMID: 20350999 |
Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. | Heidorn SJ | Cell | 2010 | PMID: 20141835 |
Insights into the molecular function of the inactivating mutations of B-Raf involving the DFG motif. | Moretti S | Biochimica et biophysica acta | 2009 | PMID: 19735675 |
Clinical biomarkers in oncology: focus on colorectal cancer. | De Roock W | Molecular diagnosis & therapy | 2009 | PMID: 19537845 |
Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. | Anastasaki C | Human molecular genetics | 2009 | PMID: 19376813 |
Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Methods in enzymology | 2008 | PMID: 18413255 |
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
Determinants of BRAF mutations in primary melanomas. | Maldonado JL | Journal of the National Cancer Institute | 2003 | PMID: 14679157 |
Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. | Ikenoue T | Cancer research | 2003 | PMID: 14678966 |
Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. | Yuen ST | Cancer research | 2002 | PMID: 12438234 |
Mutations of the BRAF gene in human cancer. | Davies H | Nature | 2002 | PMID: 12068308 |
http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>T | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d88d5d7-5d83-4298-8db6-00da7b7db528 | - | - | - | - |
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Text-mined citations for rs121913338 ...
HelpRecord last updated Feb 20, 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.