ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1801A>C (p.Lys601Gln)
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.1801A>C (p.Lys601Gln)
Variation ID: 41446 Accession: VCV000041446.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q34 7: 140753334 (GRCh38) [ NCBI UCSC ] 7: 140453134 (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 May 29, 2016 Feb 14, 2024 Apr 20, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004333.6:c.1801A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Lys601Gln missense NM_001374258.1:c.1921A>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Lys641Gln missense NM_001354609.2:c.1801A>C NP_001341538.1:p.Lys601Gln missense NM_001374244.1:c.1921A>C NP_001361173.1:p.Lys641Gln missense NM_001378467.1:c.1810A>C NP_001365396.1:p.Lys604Gln missense NM_001378468.1:c.1801A>C NP_001365397.1:p.Lys601Gln missense NM_001378469.1:c.1735A>C NP_001365398.1:p.Lys579Gln missense NM_001378470.1:c.1699A>C NP_001365399.1:p.Lys567Gln missense NM_001378471.1:c.1690A>C NP_001365400.1:p.Lys564Gln missense NM_001378472.1:c.1645A>C NP_001365401.1:p.Lys549Gln missense NM_001378473.1:c.1645A>C NP_001365402.1:p.Lys549Gln missense NM_001378474.1:c.1801A>C NP_001365403.1:p.Lys601Gln missense NM_001378475.1:c.1537A>C NP_001365404.1:p.Lys513Gln missense NC_000007.14:g.140753334T>G NC_000007.13:g.140453134T>G NG_007873.3:g.176431A>C LRG_299:g.176431A>C LRG_299t1:c.1801A>C LRG_299p1:p.Lys601Gln P15056:p.Lys601Gln - Protein change
- K601Q, K564Q, K641Q, K549Q, K567Q, K579Q, K604Q, K513Q
- Other names
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- Canonical SPDI
- NC_000007.14:140753333:T:G
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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
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. |
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BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1244 | 1358 |
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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Nov 4, 2021 | RCV000034332.21 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 2, 2019 | RCV000150201.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 20, 2023 | RCV003539770.2 |
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
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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
(Mar 18, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000058307.9
First in ClinVar: Apr 04, 2013 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 02, 2019)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Cardio-facio-cutaneous syndrome (Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197131.4
First in ClinVar: Jan 30, 2015 Last updated: May 29, 2016 |
Comment:
The p.Lys601Gln variant in BRAF has been identified as de novo occurrence in 3 i ndividuals with cardio-facio-cutaneous syndrome (Sarkozy 2009, LMM data). It was … (more)
The p.Lys601Gln variant in BRAF has been identified as de novo occurrence in 3 i ndividuals with cardio-facio-cutaneous syndrome (Sarkozy 2009, LMM data). It was absent from large population studies. Computational prediction tools and in vit ro functional studies support an impact on protein function (Sarkozy 2009). The p.Lys601Gln variant has been observed as a somatic mutation in tumor specimens f rom colorectal cancer (Oliveira 2007) and melanoma (Long 2013). Furthermore, thi s variant is in the CR3 activation segment domain, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF. Th is variant has also been reported in ClinVar (Variation ID #41446). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominan t cardio-facio-cutaneous syndrome. ACMG/AMP Criteria applied: PM6_Strong, PM1, P M2, PS4_Moderate, PS3_Supporting, PP3. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329760.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies of the K601Q variant have demonstrated that it results in the enhanced phosphorylation of MEK and ERK proteins (Sarkozy et al., 2009).; … (more)
Published functional studies of the K601Q variant have demonstrated that it results in the enhanced phosphorylation of MEK and ERK proteins (Sarkozy et al., 2009).; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19206169, 26619011, 16953233, 33753861, 24803665, 33040082, 33482860, 29493581, 17603483, 15520807, 16439621, 15488754, 24957944) (less)
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Pathogenic
(Apr 20, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294692.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the BRAF protein (p.Lys601Gln). … (more)
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 601 of the BRAF protein (p.Lys601Gln). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys601 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22495831, 24451042, 28650561, 28832562). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169). 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. ClinVar contains an entry for this variant (Variation ID: 41446). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. (less)
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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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A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data. | Stark Z | European journal of human genetics : EJHG | 2017 | PMID: 28832562 |
Craniosynostosis in patients with RASopathies: Accumulating clinical evidence for expanding the phenotype. | Ueda K | American journal of medical genetics. Part A | 2017 | PMID: 28650561 |
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
Diagnosis of Noonan syndrome and related disorders using target next generation sequencing. | Lepri FR | BMC medical genetics | 2014 | PMID: 24451042 |
Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. | Long GV | The American journal of surgical pathology | 2013 | PMID: 23026937 |
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 |
Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
KRAS and BRAF oncogenic mutations in MSS colorectal carcinoma progression. | Oliveira C | Oncogene | 2007 | PMID: 16953233 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRAF | - | - | - | - |
Text-mined citations for rs121913364 ...
HelpRecord last updated Oct 08, 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.