VCV000013972.13 - ClinVar

NM_004333.6(BRAF):c.1781A>G (p.Asp594Gly)

Germline

Classification

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.

(14)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004333.6(BRAF):c.1781A>G (p.Asp594Gly)

Variation ID: 13972 Accession: VCV000013972.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 140753354 (GRCh38) [ NCBI UCSC ] 7: 140453154 (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	Jan 31, 2015	Apr 20, 2024	Aug 3, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_004333.6:c.1781A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004324.2:p.Asp594Gly	missense
NM_001374258.1:c.1901A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001361187.1:p.Asp634Gly	missense
NM_001354609.2:c.1781A>G	NP_001341538.1:p.Asp594Gly	missense
NM_001374244.1:c.1901A>G	NP_001361173.1:p.Asp634Gly	missense
NM_001378467.1:c.1790A>G	NP_001365396.1:p.Asp597Gly	missense
NM_001378468.1:c.1781A>G	NP_001365397.1:p.Asp594Gly	missense
NM_001378469.1:c.1715A>G	NP_001365398.1:p.Asp572Gly	missense
NM_001378470.1:c.1679A>G	NP_001365399.1:p.Asp560Gly	missense
NM_001378471.1:c.1670A>G	NP_001365400.1:p.Asp557Gly	missense
NM_001378472.1:c.1625A>G	NP_001365401.1:p.Asp542Gly	missense
NM_001378473.1:c.1625A>G	NP_001365402.1:p.Asp542Gly	missense
NM_001378474.1:c.1781A>G	NP_001365403.1:p.Asp594Gly	missense
NM_001378475.1:c.1517A>G	NP_001365404.1:p.Asp506Gly	missense
NC_000007.14:g.140753354T>C
NC_000007.13:g.140453154T>C
NG_007873.3:g.176411A>G
LRG_299:g.176411A>G
LRG_299t1:c.1781A>G
	P15056:p.Asp594Gly

... more HGVS ... less HGVS

Protein change

D594G, D560G, D506G, D542G, D557G, D572G, D597G, D634G

Other names

Canonical SPDI

NC_000007.14:140753353:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA123657 UniProtKB: P15056#VAR_018624 OMIM: 164757.0011 dbSNP: rs121913338 VarSome

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
Gene	OMIM	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.
Non-Hodgkin lymphoma	Pathogenic (1)	no assertion criteria provided	Nov 17, 2003	RCV000015006.10
Non-small cell lung carcinoma	Pathogenic (1)	criteria provided, single submitter	Jun 11, 2012	RCV000037932.6
B-cell chronic lymphocytic leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000418680.2
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423919.2
Lung adenocarcinoma	Likely pathogenic (2)	no assertion criteria provided	May 31, 2016	RCV000426107.3
Adrenal cortex carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433779.2
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000437006.2
Melanoma	Pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000426339.2
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000442759.2
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435875.2
Neoplasm of brain	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000443065.2
Neoplasm of the large intestine	Pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000443882.2
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 3, 2021	RCV001238853.6
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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.
Pathogenic (Jun 11, 2012)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Non-small cell lung carcinoma Affected status: not provided Allele origin: somatic	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061597.4 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Publications: PubMed (1) PubMed: 14688025 Comment: This variant has been reported as a somatic change in large intestine, skin, end ometrium, stomach, and ovary (COSMIC, Fransen 2004) and has been observed … (more) This variant has been reported as a somatic change in large intestine, skin, end ometrium, stomach, and ovary (COSMIC, Fransen 2004) and has been observed in up to 11% of BRAF mutant positive lung adenocarcinoma (Paik 2011). (less) Number of individuals with the variant: 2
Uncertain significance (Aug 03, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001411685.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 23352452‚ 29595366 Comment: This sequence change replaces aspartic acid with glycine at codon 594 of the BRAF protein (p.Asp594Gly). The aspartic acid residue is highly conserved and there … (more) This sequence change replaces aspartic acid with glycine at codon 594 of the BRAF protein (p.Asp594Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13972). 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. Experimental studies have shown that this variant affects BRAF function (PMID: 23352452, 29595366). 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. (less)
Pathogenic (Nov 17, 2003)	no assertion criteria provided Method: literature only	LYMPHOMA, NON-HODGKIN, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000035262.6 First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016	Publications: PubMed (1) PubMed: 14612909 Comment on evidence: For discussion of the asp594-to-gly (D594G) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas … (more) For discussion of the asp594-to-gly (D594G) mutation in the BRAF gene that was found in compound heterozygous state in genomic DNA from 164 non-Hodgkin lymphomas (see 605027) by Lee et al. (2003), see 164757.0009. (less)
Pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504291.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (8) PubMed: 19537845‚ 22310681‚ 12068308‚ 25157968‚ 20619739‚ 21129611‚ 26619011‚ 20350999 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504292.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Adrenal cortex carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504293.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504297.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504299.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of brain (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504294.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
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: SCV000504295.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (4) PubMed: 14679157‚ 18794803‚ 12068308‚ 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504296.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	B-cell chronic lymphocytic leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504300.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504298.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Adenocarcinoma of lung Affected status: yes Allele origin: somatic	Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University Accession: SCV004042818.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
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Comment:

This sequence change replaces aspartic acid with glycine at codon 594 of the BRAF protein (p.Asp594Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRAF-related conditions. ClinVar contains an entry for this variant (Variation ID: 13972). 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. Experimental studies have shown that this variant affects BRAF function (PMID: 23352452, 29595366). 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.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dabrafenib in combination with trametinib in the treatment of patients with BRAF V600-positive advanced or metastatic non-small cell lung cancer: clinical evidence and experience.	Khunger A	Therapeutic advances in respiratory disease	2018	PMID: 29595366
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.	Freeman AK	Molecular cell	2013	PMID: 23352452
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
Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis.	De Roock W	The Lancet. Oncology	2010	PMID: 20619739
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
Clinical biomarkers in oncology: focus on colorectal cancer.	De Roock W	Molecular diagnosis & therapy	2009	PMID: 19537845
CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations.	Smalley KS	Oncogene	2009	PMID: 18794803
Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas.	Fransén K	Carcinogenesis	2004	PMID: 14688025
Determinants of BRAF mutations in primary melanomas.	Maldonado JL	Journal of the National Cancer Institute	2003	PMID: 14679157
BRAF mutations in non-Hodgkin's lymphoma.	Lee JW	British journal of cancer	2003	PMID: 14612909
Mutations of the BRAF gene in human cancer.	Davies H	Nature	2002	PMID: 12068308
http://docm.genome.wustl.edu/variants/ENST00000288602:c.1781A>G	-	-	-	-
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Text-mined citations for rs121913338 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_004333.6(BRAF):c.1781A>G (p.Asp594Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913338 ...