Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_001354609.2 | Alternative | 9687 nt | 227–2530 |
| NM_001354609.1 | Alternative | 9702 nt | 226–2529 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThis sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the BRAF protein (p.Phe247Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRAF-related conditions (PMID: 31785789, 32005694; internal data). ClinVar contains an entry for this variant (Variation ID: 44830). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRAF protein function with a negative predictive value of 80%. This variant disrupts the p.Phe247 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28512244, 33040082, 33128510; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: BRAFF247VBRAFF247VSomaticNCBI Gene:673|Show additional gene information Variant OverviewBRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.The BRAF F247V mutation has not specifically been reviewed by the OncoKB team. However, BRAF F247L is likely oncogenic, and therefore BRAF F247V is considered likely oncogenic.Hide mutation effect description The BRAF F247V mutation has not specifically been reviewed by the OncoKB team. However, the mutation effect description for BRAF F247L, an alternate allele of BRAF F247V, is: The class III BRAF F247L mutation is located in the RAS binding and kinase autoinhibitory domain of the BRAF protein (PMID: 31515458). This mutation has been found in colorectal cancers, among others (PMID: 31515458). In vitro studies have demonstrated that this mutation is activating as measured by increased downstream signaling compared to wildtype (PMID: 28512244, 29533785). A patient with metastatic colorectal cancer harboring BRAF F247L was treated with a combination therapy of FOLFIRI plus cetuximab and demonstrated a complete response with a progression-free survival of 12.6 months (PMID: 31515458). JAX-CKB: No results found
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.2 | -21 bp |
| Donor Loss (DL) | 0.0 | 28 bp |
| Acceptor Gain (AG) | 0.0 | 27 bp |
| Donor Gain (DG) | 0.0 | -121 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)