About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1330C>T, p.(Arg444Trp)
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
PM1Moderate
PM1 · moderate
Variant c.1330C>T (p.Arg444Trp) is located in exon 11 (c.1315-1432), which is a VCEP-designated critical and well-established functional domain for BRAF. PM1 applied at Moderate strength per RASopathy VCEP v2.3.0 rule: 'Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]).'
PP2Supporting
PP2 · supporting
BRAF gnomAD missense Z-score is well above 3.09, meeting VCEP PP2 criteria at Supporting strength. BRAF is highly constrained against missense variation in the general population, consistent with its role as a proto-oncogene where gain-of-function missense variants cause 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: PM1 moderate, 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
1 / 1,613,628 alleles
gnomAD v4.1: 1 / 1,613,628 alleles. Recorded AF 6.19722e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89235e-05; MAF= 0.00289%, 1/34574 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.090 maximum delta
Recorded SpliceAI maximum delta score: 0.090. 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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56083156, n = 3 times).
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.
26 criteria with recorded statuses: 2 met · 8 not met · 10 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM1 (Moderate) is met: variant c.1330C>T (p.Arg444Trp) is located in exon 11, a VCEP-designated critical functional domain for BRAF per RASopathy VCEP v2.3.0.
PP2 (Supporting) is met: BRAF gnomAD missense Z-score exceeds 3.09, indicating strong purifying selection against missense variation, consistent with a gene where missense variants are a common mechanism of RASopathy disease.
PM2 is not met: the variant is present in gnomAD v2.1 (1/251,378) and v4.1 (1/1,613,628), which precludes application under the VCEP rule requiring absence from controls.
PP3 is not met: REVEL score (0.637) falls below the VCEP PP3 threshold of ≥0.7, and SpliceAI (max delta 0.09) predicts no splicing impact.
No benign criteria are met. BA1 and BS1 are not met (allele frequency far below population thresholds). BP4 is not met (REVEL 0.637 > 0.3 threshold).
Under RASopathy VCEP v2.3.0 combination rules, PM1_Moderate + PP2_Supporting does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule. The minimum for Likely Pathogenic requires either 1 Strong + 1 Moderate, or ≥3 Moderate, or 1 Moderate + ≥4 Supporting criteria. Final classification: Variant of Uncertain Significance (VUS).
PVS1, PS5, PP4, PP5, BS3, BP6 are not applicable under the VCEP framework. PS1, PS2, PS3, PS4, PM5, PM6, PP1, BS2, BS4, BP2, BP5 are not assessed due to absence of data. PM2, PP3, BA1, BS1, BP1, BP4, BP7 were assessed and not met.
Three ClinVar-attached PMIDs (25394175, 31829902, 35924163) were reviewed in full text; none mention NM_004333.5:c.1330C>T or p.Arg444Trp. These papers are clinical practice guidelines or consensus statements on cancer genetics referral and prostate cancer biomarkers and do not provide variant-specific evidence.
No criteria match.
Met · 2
PM1 ModerateVariant c.1330C>T (p.Arg444Trp) is located in exon 11 (c.1315-1432), which is a VCEP-designated critical and well-established functional domain for BRAF. PM1 applied at Moderate strength per RASopathy VCEP v2.3.0 rule: 'Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]).' Details ▾Hide ▴
Evidence considered
- c.1330C>T falls within exon 11 (c.1315-1432 per Mutalyzer exon coordinates)
- exon 11 is a VCEP-specified critical domain.
Sources
PP2 SupportingBRAF gnomAD missense Z-score is well above 3.09, meeting VCEP PP2 criteria at Supporting strength. BRAF is highly constrained against missense variation in the general population, consistent with its role as a proto-oncogene where gain-of-function missense variants cause RASopathies. Details ▾Hide ▴
Evidence considered
- BRAF gnomAD v2.1 missense Z-score exceeds 3.09 threshold (BRAF is highly missense-constrained per gnomAD constraint metrics).
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No evidence that Arg444Trp has been previously established as pathogenic via a different nucleotide change at the same residue. Not observed in any curated VCEP-approved assay or published pathogenic assertion. Details ▾Hide ▴
PM2 VCEP PM2 rule requires the variant to be absent from gnomAD. This variant is present in gnomAD v2.1 (1/251,378 alleles, AF=3.98e-06) and gnomAD v4.1 (1/1,613,628 alleles, AF=6.20e-07). Presence in population databases precludes PM2 application under VCEP. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AC=1
- AN=251
- 378
- AF=3.98e-06
- gnomAD v4.1: AC=1
- AN=1
- 613
- 628
- AF=6.20e-07. VCEP PM2 requires absence.
Sources
PP3 VCEP PP3 requires REVEL score ≥ 0.7 for missense variants. REVEL score for p.Arg444Trp is 0.637, below the VCEP threshold. SpliceAI predicts no significant splice impact (max delta = 0.09). Details ▾Hide ▴
Evidence considered
- REVEL=0.637 (<0.7 threshold)
- SpliceAI max delta=0.09
- BayesDel=0.258.
Sources
BA1 VCEP BA1 requires gnomAD filtering allele frequency ≥ 0.05%. Highest observed subpopulation AF is 2.89e-05 (0.0029%) in Admixed American (v2.1), far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpop AF=2.89e-05 (Admixed American
- 1/34
- 574)
- gnomAD v4.1 max subpop AF=1.67e-05 (Admixed American
- 1/59
- 980). Both well below 0.05% BA1 threshold.
Sources
BS1 VCEP BS1 requires gnomAD filtering allele frequency ≥ 0.025%. The variant's maximum subpopulation AF (2.89e-05) is roughly 10-fold below this threshold. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF=2.89e-05 (v2.1 Admixed American)
- well below 0.025% BS1 threshold.
Sources
BP1 VCEP BP1 applies only to truncating variants (nonsense, frameshift, canonical splice, initiation codon, whole/multi-exon deletion) in genes where primarily missense GOF variants cause disease. This is a missense variant. Details ▾Hide ▴
Evidence considered
- c.1330C>T is a missense variant (p.Arg444Trp)
- BP1 applies only to truncating variants.
Sources
BP4 VCEP BP4 requires REVEL ≤ 0.3 for missense variants. REVEL score is 0.637, above this threshold. Multiple computational tools (REVEL 0.637, BayesDel 0.258) do not uniformly suggest no impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.637 (>0.3 BP4 threshold)
- BayesDel=0.258 (below typical deleterious threshold but above BP4 cutoff)
- SpliceAI max delta=0.09 (no splicing impact).
Sources
BP7 VCEP BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. c.1330C>T is a missense variant (p.Arg444Trp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- BP7 applies to synonymous variants only.
Sources
Not assessed · 10 · no assessment recorded
PS2 No de novo data available for this variant. VCEP PS2 uses point-based de novo scoring requiring confirmed parentage and RASopathy phenotype. Details ▾Hide ▴
Evidence considered
- No de novo observations in available data sources.
Still missing
- No de novo testing data available.
Sources
PS3 Variant not tested in any VCEP-approved functional assays. No variant-specific functional data identified in the literature or functional studies spreadsheet. Details ▾Hide ▴
Evidence considered
- SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx reviewed
- R444W not present in any approved assay (BRAF Kinase Activity
- MEK Activation
- ERK Activation
- RAS Activation
- etc.).
Still missing
- No functional data available for p.Arg444Trp in VCEP-approved assays or published literature.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No proband case counts or case-control data available. ClinVar submission audit yielded zero usable submissions for classification. VCEP PS4 uses a point-based scoring system requiring proband observations. Details ▾Hide ▴
PM5 VCEP PM5 requires at least one [likely] pathogenic residue change at the same codon (444). No other pathogenic or likely pathogenic missense variant at codon 444 has been identified. PM5 candidates search returned zero candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection returned zero same-residue candidates at codon 444. No ClinVar P/LP submissions at this residue.
Still missing
- No known pathogenic missense variant at codon 444.
Sources
cspec ↗pm5_candidates
PM6 No de novo data available. VCEP PM6 uses point-based de novo scoring; no de novo observations identified. Details ▾Hide ▴
Evidence considered
- No de novo reports for this variant in any data source.
Still missing
- No de novo data available.
Sources
PP1 No cosegregation data available. VCEP PP1 requires informative meioses with RASopathy phenotype. Details ▾Hide ▴
Evidence considered
- No family segregation data in any source.
Still missing
- No segregation data.
Sources
BS2 VCEP BS2 uses a point-based scoring system requiring observation in a healthy adult for a fully penetrant disorder. No data available to assess this criterion. Details ▾Hide ▴
Evidence considered
- No evidence of observation in healthy adult individuals with adequate phenotypic data.
Still missing
- No data on healthy adult carriers.
Sources
BS4 VCEP BS4 assesses lack of segregation in affected family members. No segregation data available. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data.
Sources
BP2 VCEP BP2 uses point-based scoring for an alternative molecular cause of a RASopathy in the same gene. No data on co-occurring variants available. Details ▾Hide ▴
Evidence considered
- No evidence of alternative molecular cause in cis/trans.
Still missing
- No co-occurring variant data.
Sources
BP5 VCEP BP5 uses point-based scoring for an alternative molecular cause of a RASopathy in a different gene. No data available. Details ▾Hide ▴
Evidence considered
- No evidence of alternative molecular basis for disease.
Still missing
- No alternative molecular diagnosis data.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPVCEP criterion not applicable (missense variant, not a null variant); confirmed by RASopathy VCEP v2.3.0 PVS1 applicability designation. Details ▾Hide ▴
PP4 VCEPVCEP PP4 is Not Applicable per RASopathy VCEP v2.3.0; see PS4 instead. Details ▾Hide ▴
PP5 VCEPPP5 is not for use per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation and is designated 'Not Applicable' in RASopathy VCEP v2.3.0. Details ▾Hide ▴
BS3 VCEPVCEP BS3 is Not Applicable per RASopathy VCEP v2.3.0. Details ▾Hide ▴
BP6 VCEPBP6 is not for use per ClinGen Sequence Variant Interpretation VCEP Review Committee and is designated 'Not Applicable' in RASopathy VCEP v2.3.0. Details ▾Hide ▴
PS5 N/APS5 is not a criterion in the ClinGen RASopathy VCEP v2.3.0 framework. Under VCEP mode, only VCEP-defined criteria are applied. Details ▾Hide ▴
Identifiers
- Gene
- BRAF
- Transcript
- NM_004333.5
- Coding (HGVS c.)
- NM_004333.5:c.1330C>T
- Protein (HGVS p.)
- NP_004324.2:p.(Arg444Trp)
- GRCh38
- chr7:140781678 G>A
- GRCh37
- chr7:140481478 G>A
- ClinVar
- 1711755
- COSMIC
- COSV56083156
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
1 / 1,613,628 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,378 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,628 alleles · 0 hom
| Admixed American1 / 59,980 | 1.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,378 alleles · 0 hom
| Admixed American1 / 34,574 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19722e-07; MAF= 0.00006%, 1/1613628 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66722e-05; MAF= 0.00167%, 1/59980 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89235e-05; MAF= 0.00289%, 1/34574 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.637
- BayesDel
- 0.258
How the predictions were used
PP3 VCEP PP3 requires REVEL score ≥ 0.7 for missense variants. REVEL score for p.Arg444Trp is 0.637, below the VCEP threshold. SpliceAI predicts no significant splice impact (max delta = 0.09). Details ▾Hide ▴
Evidence considered
- REVEL=0.637 (<0.7 threshold)
- SpliceAI max delta=0.09
- BayesDel=0.258.
Sources
BP4 VCEP BP4 requires REVEL ≤ 0.3 for missense variants. REVEL score is 0.637, above this threshold. Multiple computational tools (REVEL 0.637, BayesDel 0.258) do not uniformly suggest no impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.637 (>0.3 BP4 threshold)
- BayesDel=0.258 (below typical deleterious threshold but above BP4 cutoff)
- SpliceAI max delta=0.09 (no splicing impact).
Sources
BP7 VCEP BP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. c.1330C>T is a missense variant (p.Arg444Trp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- BP7 applies to synonymous variants only.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.637. BayesDel score = 0.25761.
3 paper records 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 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Provides referral criteria for hereditary cancer syndromes but does not discuss BRAF c.1330C>T or p.Arg444Trp.Does not name this variant
Quoted passage
in KIT, PDGFRA, or BRAF. Of patients with sporadic wild-type
Gene-level mention of BRAF at line 842 as part of a list: 'in KIT, PDGFRA, or BRAF.'
-
PMID 31829902 ↗Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline.Eggener SE et al. · 2020ASCO guideline on molecular biomarkers in localized prostate cancer. Discusses tissue-based biomarkers (Oncotype Dx, Prolaris, Decipher, ProMark) for risk stratification. Does not discuss BRAF, c.1330C>T, or p.Arg444Trp.Does not name this variant
-
PMID 35924163 ↗Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology.Chiu PKF et al. · 2022Consensus statement from Hong Kong Urological Association and Hong Kong Society of Uro-Oncology on genetic testing in prostate cancer management. Mentions RAS/RAF/MEK pathway at the gene level but does not discuss BRAF c.1330C>T or p.Arg444Trp.Does not name this variant
Quoted passage
genomic profiling should be performed by NGS panel that covers the potentially actionable targets in PC such as DNA damage repair (HRR, MMR and Fanconi anemia genes, and CDK12), phosphatidylinositol-3-kinase (PI3K), and RAS/RAF/MEK pathways.
Statement 2.3.1 mentions 'RAS/RAF/MEK pathways' as part of genomic profiling recommendations.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,628 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.090
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.1330C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140481478-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140781678-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-140781678-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004333.5%3Ac.1330…
- OncoKB ↗www.oncokb.org/gene/BRAF/R444W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=221487040
- 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
This variant is present in gnomAD v4.1 (AF= 6.19722e-07; MAF= 0.00006%, 1/1613628 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66722e-05; MAF= 0.00167%, 1/59980 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97807e-06; MAF= 0.00040%, 1/251378 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89235e-05; MAF= 0.00289%, 1/34574 alleles, homozygotes = 0).
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 = 0.09). REVEL score = 0.637. BayesDel score = 0.25761.
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 previously been reported in somatic cancers (COSMIC; COSV56083156, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.