About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.2107G>A, p.(Glu703Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen BRAF VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting rule requiring absence from population controls.
PP2Supporting
PP2 · supporting
BRAF has a gnomAD missense Z-score >3.09, meeting the VCEP PP2 rule. BRAF is a well-established gene with low tolerance for benign missense variation, and missense variants are a common mechanism of disease in RASopathies.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRAF VCEP v2.3.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004333.5:c.2107G>A (p.Glu703Lys) is a missense variant in BRAF exon 17, within the C-terminal lobe of the kinase domain but outside all VCEP-specified PM1 critical functional domains (P-loop AA 459-474, CR3 activation segment AA 594-627).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under the RASopathy VCEP.
BRAF has a gnomAD missense Z-score >3.09, meeting PP2 at supporting strength, consistent with low tolerance for benign missense variation in this gene.
The REVEL score of 0.579 does not meet the VCEP thresholds for PP3 (≥0.7) or BP4 (≤0.3), and SpliceAI predicts no splice impact (max delta 0.06). Computational evidence is indeterminate.
No functional data exists for p.Glu703Lys in any VCEP-approved assay (BRAF Kinase, MEK Activation, ERK Activation); the variant is not listed in the SVI functional studies spreadsheet. OncoKB reports Unknown Oncogenic Effect.
No same-codon pathogenic comparator exists at residue 703 (PM5), no de novo observations have been reported (PS2/PM6), no case-control or segregation data is available (PS4/PP1), and no prior pathogenic assertion for E703K exists (PS1).
ClinVar reports a single submitter classifying the variant as Uncertain Significance (Variation ID 4856330, criteria provided, single submitter). PP5 and BP6 are not applicable under this VCEP.
The only met criteria are PM2_Supporting and PP2_Supporting. No pathogenic criteria at moderate, strong, or very strong level are met. Under the RASopathy VCEP combination rules, this evidence is insufficient to classify the variant as Pathogenic or Likely Pathogenic, and insufficient benign evidence exists to classify as Benign or Likely Benign. The variant remains a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting rule requiring absence from population controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
PP2 SupportingBRAF has a gnomAD missense Z-score >3.09, meeting the VCEP PP2 rule. BRAF is a well-established gene with low tolerance for benign missense variation, and missense variants are a common mechanism of disease in RASopathies. Details ▾Hide ▴
Evidence considered
- BRAF gnomAD missense Z-score exceeds 3.09 (gene is highly constrained for missense variation).
Still missing
- Direct gnomAD constraint metric retrieval was not available in case materials
- relies on established public knowledge of BRAF constraint.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change to have been previously established as pathogenic. The variant p.Glu703Lys has not been established as pathogenic; ClinVar reports a single submitter classifying it as Uncertain Significance. No prior pathogenic assertion exists for E703K in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter
- Uncertain Significance classification for E703K (Variation ID 4856330). No prior pathogenic assertion for this amino acid change.
Sources
PS2 No de novo occurrence of NM_004333.5:c.2107G>A has been reported. The literature and ClinVar submissions contain no confirmed de novo observations for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or case data.
Still missing
- No proband data available to assess de novo status.
PS3 No functional data exists for p.Glu703Lys in any VCEP-approved assay (BRAF Kinase Activity, MEK Activation Assay, ERK Activation Assay). The variant is not listed among validation controls or tested variants in the SVI-RASopathy-VCEP-V2-Approved-Functional-Studies spreadsheet. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- VCEP functional studies spreadsheet: E703K not listed in any BRAF assay (Kinase
- MEK
- ERK).
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No experimental functional characterization of p.Glu703Lys has been published.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
PS4 No case-control data or proband counts are available for NM_004333.5:c.2107G>A. The variant has not been reported in affected individuals beyond the single ClinVar submission, which lacks phenotypic details. Insufficient evidence to meet any PS4 point threshold under the RASopathy VCEP. Details ▾Hide ▴
Evidence considered
- ClinVar: single submission with no clinical assertions beyond VUS classification.
Still missing
- No proband counts or case-control data available.
Sources
PM1 PM1 under the RASopathy VCEP is restricted to exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627). The variant p.Glu703Lys lies in exon 17 within the C-terminal lobe of the kinase domain, outside all VCEP-specified PM1 domains. It is also not located in a statistically significant cancer hotspot per cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domains: exon 6
- exon 11
- P-loop (459-474)
- CR3 activation segment (594-627). Position 703 is in exon 17
- outside all domains.
- Cancer Hotspots: residue 703 is not a statistically significant hotspot.
Sources
PM5 PM5 under the RASopathy VCEP requires at least one [likely] pathogenic residue change at the same codon. No other missense change at codon 703 has been reported as pathogenic or likely pathogenic in ClinVar. The only variant at this codon is E703K itself (VUS). Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-codon [likely] pathogenic comparators found at residue 703.
- ClinVar: only E703K reported at codon 703
- classified as VUS.
Sources
pm5_candidatesclinvar ↗
PM6 No assumed de novo observation (without confirmed parentage) has been reported for NM_004333.5:c.2107G>A. No proband data with parental genotypes is available. Details ▾Hide ▴
Evidence considered
- No de novo or assumed de novo reports identified.
Still missing
- No proband or parental genotype data available.
PP1 No co-segregation data is available for NM_004333.5:c.2107G>A. No family studies with this variant have been reported. Details ▾Hide ▴
Evidence considered
- No segregation data identified in literature or case materials.
Still missing
- No family studies or co-segregation data available.
PP3 The REVEL score for this variant is 0.579, below the VCEP PP3 threshold of REVEL ≥0.7. SpliceAI predicts no splice impact (max delta score 0.06). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.579 (threshold for PP3 is ≥0.7).
- SpliceAI max delta: 0.06 (no significant splice impact).
- BayesDel: 0.046 (adds no additional support).
Sources
BA1 BA1 under the RASopathy VCEP requires a gnomAD filtering allele frequency ≥0.05%. The variant is absent from all gnomAD populations, falling far below this threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- allele frequency is 0
- below the 0.05% BA1 threshold.
Sources
BS1 BS1 under the RASopathy VCEP requires a gnomAD filtering allele frequency ≥0.025%. The variant is absent from all gnomAD populations, falling below this threshold. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- allele frequency is 0
- below the 0.025% BS1 threshold.
Sources
BS2 No observations of this variant in healthy adult individuals have been reported. No data available to satisfy BS2 point-based scoring under the RASopathy VCEP. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier observations available.
Still missing
- No healthy control data with this variant available.
BS4 No segregation data is available to demonstrate lack of segregation in affected family members. The VCEP requires only one informative meiosis for BS4, but no family data exists for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family studies to assess BS4.
BP2 No evidence of an alternative molecular cause of a RASopathy in the same gene has been identified. No data available to satisfy BP2 point-based scoring. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause in BRAF identified.
Still missing
- No co-occurring variant data available.
BP4 BP4 under the RASopathy VCEP requires a REVEL score ≤0.3 for missense variants. The REVEL score for this variant is 0.579, which does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
- REVEL: 0.579 (threshold for BP4 is ≤0.3).
- SpliceAI max delta: 0.06 (no splicing impact
- but REVEL does not support benign prediction).
Sources
revelspliceai ↗
BP5 No evidence of an alternative molecular cause of a RASopathy in a different gene has been identified. No data available to satisfy BP5 point-based scoring. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause in a different gene identified.
Still missing
- No co-occurring variant data in other RASopathy genes available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable under the ClinGen RASopathy VCEP for BRAF (version 2.3.0); the variant is a missense substitution (c.2107G>A, p.Glu703Lys) and does not meet the null-variant criteria of nonsense, frameshift, or canonical splice site alteration. Details ▾Hide ▴
Evidence considered
- CSPEC/VCEP explicitly designates PVS1 as Not Applicable for this gene framework.
Sources
PM3 VCEPPM3 applies to recessive disorders (detected in trans with a pathogenic variant). RASopathies are autosomal dominant; this criterion is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This variant is a missense substitution and does not alter protein length. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPPP4 is designated as Not Applicable by the ClinGen RASopathy VCEP for BRAF (version 2.3.0). The VCEP directs users to PS4 instead. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the RASopathy VCEP framework. Details ▾Hide ▴
Evidence considered
- CSPEC/VCEP: PP5 Not Applicable per ClinGen SVI VCEP Review Committee recommendation.
Sources
BS3 VCEPBS3 is designated as Not Applicable by the ClinGen RASopathy VCEP for BRAF (version 2.3.0). Details ▾Hide ▴
BP1 N/ABP1 under the RASopathy VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, whole-gene or multi-exon deletions) in genes where the disease mechanism is gain-of-function. NM_004333.5:c.2107G>A is a missense variant and does not meet the truncating variant requirement for BP1. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule: restricted to truncating variants
- this is a missense substitution.
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the RASopathy VCEP framework. Details ▾Hide ▴
Evidence considered
- CSPEC/VCEP: BP6 Not Applicable per ClinGen SVI VCEP Review Committee recommendation.
Sources
BP7 N/ABP7 under the RASopathy VCEP applies to synonymous (silent) variants and intronic positions outside canonical splice sites. NM_004333.5:c.2107G>A is a missense variant (p.Glu703Lys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule: restricted to synonymous/intronic variants
- this is a missense substitution.
Sources
PS5 N/APS5 is not defined in the ClinGen RASopathy VCEP criteria set for BRAF (version 2.3.0). No VCEP rule exists for this criterion. Details ▾Hide ▴
Identifiers
- Gene
- BRAF
- Transcript
- NM_004333.5
- Coding (HGVS c.)
- NM_004333.5:c.2107G>A
- Protein (HGVS p.)
- NP_004324.2:p.(Glu703Lys)
- GRCh38
- chr7:140739832 C>T
- GRCh37
- chr7:140439632 C>T
- ClinVar
- 4856330
Gene diagram
Every interpreted variant in BRAF, mapped onto the exon structure of NM_004333.5. Select a row to find it on the plot.
BRAFNM_004333.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRAF
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.579
- BayesDel
- 0.046
How the predictions were used
PP3 The REVEL score for this variant is 0.579, below the VCEP PP3 threshold of REVEL ≥0.7. SpliceAI predicts no splice impact (max delta score 0.06). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.579 (threshold for PP3 is ≥0.7).
- SpliceAI max delta: 0.06 (no significant splice impact).
- BayesDel: 0.046 (adds no additional support).
Sources
BP4 BP4 under the RASopathy VCEP requires a REVEL score ≤0.3 for missense variants. The REVEL score for this variant is 0.579, which does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
- REVEL: 0.579 (threshold for BP4 is ≤0.3).
- SpliceAI max delta: 0.06 (no splicing impact
- but REVEL does not support benign prediction).
Sources
revelspliceai ↗
BP7 N/ABP7 under the RASopathy VCEP applies to synonymous (silent) variants and intronic positions outside canonical splice sites. NM_004333.5:c.2107G>A is a missense variant (p.Glu703Lys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule: restricted to synonymous/intronic variants
- this is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.579. BayesDel score = 0.0458388.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP standards and guidelines for sequence variant interpretation. The paper provides the methodological framework for variant classification and does not discuss any specific variants or genes.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.060
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243119
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004333.5%3Ac.2107G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140439632-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140739832-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-140739832-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004333.5%3Ac.2107…
- OncoKB ↗www.oncokb.org/gene/BRAF/E703K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.2107G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.579. BayesDel score = 0.0458388.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.