VCV000376073.8 - ClinVar

NM_004333.6(BRAF):c.1397G>A (p.Gly466Glu)

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.

(9)

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
Likely 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.1397G>A (p.Gly466Glu)

Variation ID: 376073 Accession: VCV000376073.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q34 7: 140781611 (GRCh38) [ NCBI UCSC ] 7: 140481411 (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	Mar 8, 2017	Feb 14, 2024	Jan 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004333.6:c.1397G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004324.2:p.Gly466Glu	missense
NM_001374258.1:c.1517G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001361187.1:p.Gly506Glu	missense
NM_001354609.2:c.1397G>A	NP_001341538.1:p.Gly466Glu	missense
NM_001374244.1:c.1517G>A	NP_001361173.1:p.Gly506Glu	missense
NM_001378467.1:c.1406G>A	NP_001365396.1:p.Gly469Glu	missense
NM_001378468.1:c.1397G>A	NP_001365397.1:p.Gly466Glu	missense
NM_001378469.1:c.1331G>A	NP_001365398.1:p.Gly444Glu	missense
NM_001378470.1:c.1295G>A	NP_001365399.1:p.Gly432Glu	missense
NM_001378471.1:c.1286G>A	NP_001365400.1:p.Gly429Glu	missense
NM_001378472.1:c.1241G>A	NP_001365401.1:p.Gly414Glu	missense
NM_001378473.1:c.1241G>A	NP_001365402.1:p.Gly414Glu	missense
NM_001378474.1:c.1397G>A	NP_001365403.1:p.Gly466Glu	missense
NM_001378475.1:c.1133G>A	NP_001365404.1:p.Gly378Glu	missense
NC_000007.14:g.140781611C>T
NC_000007.13:g.140481411C>T
NG_007873.3:g.148154G>A
LRG_299:g.148154G>A

... more HGVS ... less HGVS

Protein change

G466E, G378E, G414E, G429E, G432E, G444E, G469E, G506E

Other names

Canonical SPDI

NC_000007.14:140781610:C:T

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: CA16602535 dbSNP: rs121913351 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.
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000424079.1
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000427285.1
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000431475.1
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000434755.1
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000437081.1
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000442274.1
Melanoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000443232.1
RASopathy	Uncertain significance (1)	criteria provided, single submitter	Feb 14, 2021	RCV001861476.6
Noonan syndrome 7	Likely pathogenic (1)	criteria provided, single submitter	Jan 23, 2023	RCV003128083.1

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 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 (Jan 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 7 Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV003804259.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023
Uncertain significance (Feb 14, 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: SCV002171637.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 21062266‚ 31336229 Comment: This variant has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 21062266). ClinVar contains an entry for this variant (Variation ID: 376073). In summary, the … (more) This variant has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 21062266). ClinVar contains an entry for this variant (Variation ID: 376073). 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 disrupts the p.Gly466 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been observed in individuals with BRAF-related conditions (PMID: 31336229), which suggests that this may be a clinically significant amino acid residue. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 466 of the BRAF protein (p.Gly466Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. (less)
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: SCV000505041.1 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.1397G>A
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: SCV000505044.1 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.1397G>A
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: SCV000505042.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 25157968‚ 23273605 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000288602:c.1397G>A
Likely 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: SCV000505043.1 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.1397G>A
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: SCV000505045.1 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.1397G>A
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: SCV000505046.1 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.1397G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000505047.1 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.1397G>A

Comment:

This variant has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 21062266). ClinVar contains an entry for this variant (Variation ID: 376073). 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 disrupts the p.Gly466 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been observed in individuals with BRAF-related conditions (PMID: 31336229), which suggests that this may be a clinically significant amino acid residue. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 466 of the BRAF protein (p.Gly466Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid.

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
Antenatal diagnosis of cardio-facio-cutaneous syndrome: Prenatal characteristics and contribution of fetal facial dysmorphic signs in utero. About a case and review of literature.	Biard JM	European journal of obstetrics, gynecology, and reproductive biology	2019	PMID: 31336229
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
Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma.	Greaves WO	The Journal of molecular diagnostics : JMD	2013	PMID: 23273605
Dermatological findings in 61 mutation-positive individuals with cardiofaciocutaneous syndrome.	Siegel DH	The British journal of dermatology	2011	PMID: 21062266
http://docm.genome.wustl.edu/variants/ENST00000288602:c.1397G>A	-	-	-	-

Text-mined citations for rs121913351 ...

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.1397G>A (p.Gly466Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121913351 ...