About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1661T>C, p.(Ile554Thr)
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
PP2Supporting
PP2 · supporting
BRAF has a high missense constraint in gnomAD with a missense Z-score well above 3.09, meeting the VCEP threshold. BRAF has a low rate of benign missense variation and missense variants are a common mechanism of disease in RASopathies.
PP3Supporting
PP3 · supporting
REVEL score of 0.885 meets the VCEP threshold of ≥0.7 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00), and the variant is not in a splicing-relevant context. BayesDel score is 0.301 (intermediate).
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: PP2 supporting, PP3 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
23 / 1,613,478 alleles
gnomAD v4.1: 23 / 1,613,478 alleles. Recorded AF 1.42549e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97867e-06; MAF= 0.00040%, 1/251340 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Likely benign · 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56430604, n = 2 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.
29 criteria with recorded statuses: 2 met · 17 not met · 0 not assessed · 10 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.1661T>C (p.Ile554Thr) is a missense variant in BRAF exon 13, located in the kinase domain between the P-loop and CR3 activation segment.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,340 alleles) and v4.1 AF=1.43e-5 (23/1,613,478 alleles), with no homozygotes observed.
ClinVar reports conflicting interpretations: Likely benign (2 clinical laboratories) and Uncertain significance (1 clinical laboratory), with no expert panel review (ClinVar Variation ID 239870).
PP3 (supporting): REVEL score of 0.885 exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no splicing impact (max delta 0.00).
PP2 (supporting): BRAF has a high missense constraint Z-score in gnomAD (>3.09), indicating a low rate of benign missense variation consistent with a gene where missense variants are a common disease mechanism.
PM1 is not met because amino acid 554 lies outside the VCEP-specified domains (exon 6, exon 11, P-loop AA 459-474, CR3 activation segment AA 594-627).
PM2 is not met because the RASopathy VCEP requires absence from gnomAD controls, and this variant is observed in both gnomAD v2.1 and v4.1.
PM5 is not met because no other [likely] pathogenic missense variant at codon 554 was identified in ClinVar or the VCEP supplementary materials.
BS1 is not met because the allele frequency (max 9.92e-5) is below the VCEP threshold of ≥0.025%.
No benign criteria are met. Two pathogenic supporting criteria (PP2, PP3) are met. Under the RASopathy VCEP v2.3.0 combination rules, this does not reach the threshold for Likely Pathogenic (which requires at minimum 1 moderate + 4 supporting, or 1 strong + 1 moderate, or comparable combinations).
Insufficient evidence exists to classify this variant as either pathogenic or benign. With only two supporting-level pathogenic criteria and no benign criteria, this variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PP2 SupportingBRAF has a high missense constraint in gnomAD with a missense Z-score well above 3.09, meeting the VCEP threshold. BRAF has a low rate of 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 threshold
- gene has low rate of benign missense variation consistent with established RASopathy mechanism
Sources
PP3 SupportingREVEL score of 0.885 meets the VCEP threshold of ≥0.7 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00), and the variant is not in a splicing-relevant context. BayesDel score is 0.301 (intermediate). Details ▾Hide ▴
Evidence considered
- REVEL = 0.885 (≥0.7 threshold met)
- SpliceAI max delta = 0.00 (no splice impact)
- BayesDel = 0.301
Sources
Not met · 17 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change (p.Ile554Thr) via a different nucleotide change was identified in ClinVar, the VCEP functional studies spreadsheet, or the literature reviewed. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 239870 does not contain a pathogenic assertion for p.Ile554Thr from a different nucleotide change
Still missing
- No known pathogenic I554T from alternative nucleotide change identified
Sources
PS2 No de novo occurrence reports were identified for NM_004333.5:c.1661T>C in the ClinVar submissions, literature abstracts, or full-text publications reviewed. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar submissions (SCV000288406
- SCV006109060) or literature
Still missing
- No de novo data available
Sources
PS3 No variant-specific functional data were identified for p.Ile554Thr in the VCEP-approved functional studies spreadsheet (BRAF Kinase Activity, MEK/ERK Activation assays) or in the reviewed literature. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- VCEP functional studies spreadsheet contains no data for I554T
- OncoKB classifies as Unknown Oncogenic Effect with no variant-specific evidence
Still missing
- No approved functional assay data for I554T
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
PS4 No case-control or proband count data are available for NM_004333.5:c.1661T>C. The VCEP PS4 point-based system requires proband counts that are not available from the current evidence. Details ▾Hide ▴
Evidence considered
- ClinVar shows 3 submissions with conflicting classifications (2 Likely benign
- 1 Uncertain significance) but no proband counts suitable for PS4 scoring
Still missing
- No RASopathy proband counts or case-control data available
Sources
PM1 Amino acid position 554 lies outside the VCEP-specified critical functional domains for PM1 application. The RASopathy VCEP restricts PM1 to exon 6, exon 11, the P-loop (AA 459-474), and the CR3 activation segment (AA 594-627). Position 554 is in exon 13 between these domains. Details ▾Hide ▴
Evidence considered
- VCEP specification limits PM1 to exon 6
- exon 11
- P-loop (AA 459-474)
- and CR3 activation segment (AA 594-627)
- AA 554 is not in any of these domains
Sources
PM2 The RASopathy VCEP requires the variant to be absent from gnomAD controls for PM2 application. NM_004333.5:c.1661T>C is present in gnomAD v2.1 (1/251,340 alleles, AF=3.98e-6) and v4.1 (23/1,613,478 alleles, AF=1.43e-5), and therefore does not meet the absence requirement. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 340 alleles (AF=3.98e-6)
- gnomAD v4.1: 23/1
- 613
- 478 alleles (AF=1.43e-5)
Sources
PM5 PM5 requires at least one [likely] pathogenic residue change at the same codon (position 554). No such comparator variant was identified in ClinVar, the VCEP RAF-Alignment spreadsheet, or the literature reviewed. The pm5_candidates automated search returned no candidates. Details ▾Hide ▴
Evidence considered
- No [likely] pathogenic missense variant at codon 554 identified in ClinVar
- VCEP spreadsheets
- or literature
Still missing
- No comparator pathogenic variant at BRAF codon 554
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observations with confirmed or unconfirmed parentage were identified for NM_004333.5:c.1661T>C in the reviewed evidence. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
Still missing
- No de novo data
Sources
PP1 No co-segregation data are available for NM_004333.5:c.1661T>C. The VCEP requires ≥3 informative meioses for supporting-level application. Details ▾Hide ▴
Evidence considered
- No segregation data in any reviewed source
Still missing
- No family segregation data available
BA1 The gnomAD filtering allele frequency is well below the VCEP BA1 threshold of ≥0.05%. The maximum observed population frequency is 9.92e-5 (Ashkenazi Jewish, v2.1) and the grpmax FAF in v4.1 is 8.78e-6. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max pop AF = 9.92e-5 (Ashkenazi Jewish)
- gnomAD v4.1 grpmax FAF = 8.78e-6
- both well below 0.05% BA1 threshold
Sources
BS1 The gnomAD filtering allele frequency is below the VCEP BS1 threshold of ≥0.025%. The total AF in v2.1 is 3.98e-6 and in v4.1 is 1.43e-5. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF = 3.98e-6
- gnomAD v4.1 total AF = 1.43e-5
- both below 0.025% BS1 threshold
Sources
BS2 No data are available on observation of NM_004333.5:c.1661T>C in healthy adults without a RASopathy phenotype beyond gnomAD population data. The VCEP point-based BS2 system requires documented healthy adult observations which are not available. Details ▾Hide ▴
Evidence considered
- No documented healthy adult observations with full phenotype exclusion
Still missing
- No healthy adult observational data available
BS4 No segregation data are available to assess lack of segregation in affected family members. The VCEP requires only one informative meiosis for strong-level application, but no such data exist. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available
Still missing
- No family segregation data
BP1 The RASopathy VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, whole-gene/multi-exon deletions) in genes where LOF is not an established disease mechanism. NM_004333.5:c.1661T>C is a missense variant (p.Ile554Thr) and does not meet the variant-type requirement. Details ▾Hide ▴
Evidence considered
- BP1 applies only to truncating variants per VCEP
- this is a missense variant
Sources
BP2 No evidence of an alternative molecular cause of a RASopathy in the same gene was identified. The VCEP BP2 point-based system requires documented alternative molecular diagnoses which are not available. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause identified in BRAF
Still missing
- No data on alternative molecular diagnoses
BP4 REVEL score of 0.885 exceeds the VCEP BP4 threshold of ≤0.3, indicating computational evidence does not support a benign interpretation. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
- REVEL = 0.885 (exceeds ≤0.3 threshold)
- SpliceAI max delta = 0.00
Sources
revelspliceai ↗
BP5 No evidence of an alternative molecular cause of a RASopathy in a different gene was identified. The VCEP BP5 point-based system requires documented alternative diagnoses in other genes which are not available. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause identified in another gene
Still missing
- No data on alternative molecular diagnoses in other genes
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable per the ClinGen RASopathy Expert Panel specifications for BRAF (VCEP v2.3.0). Additionally, NM_004333.5:c.1661T>C is a missense variant (p.Ile554Thr), not a null variant. Details ▾Hide ▴
Evidence considered
- VCEP BRAF specification declares PVS1 not applicable
- variant is missense
- not a null variant
Sources
PM3 VCEPSkipped per adjudication instructions; VCEP also declares PM3 not applicable for autosomal dominant RASopathy. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPThe RASopathy VCEP specification states PP4 is not applicable; see PS4 instead. Details ▾Hide ▴
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the RASopathy VCEP. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable per the ClinGen RASopathy Expert Panel specifications for BRAF (VCEP v2.3.0). Details ▾Hide ▴
BP3 VCEPSkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the RASopathy VCEP. Details ▾Hide ▴
BP7 N/ANM_004333.5:c.1661T>C is a missense variant (p.Ile554Thr), not a synonymous variant. BP7 applies only to synonymous variants and intronic/non-coding variants outside canonical splice sites. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous and non-coding variants
PS5 N/ANot in the assess list for this adjudication. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRAF
- Transcript
- NM_004333.5
- Coding (HGVS c.)
- NM_004333.5:c.1661T>C
- Protein (HGVS p.)
- NP_004324.2:p.(Ile554Thr)
- GRCh38
- chr7:140776945 A>G
- GRCh37
- chr7:140476745 A>G
- ClinVar
- 239870
- COSMIC
- COSV56430604
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
23 / 1,613,478 alleles
AF 1.43e-05 · 0 homozygotes · FAF 8.78e-06
gnomAD v2.1
1 / 251,340 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.4e-05 · 23 / 1,613,478 alleles · 0 hom · FAF 8.8e-06
| Ashkenazi Jewish1 / 29,596 | 3.4e-05 |
| South Asian3 / 91,064 | 3.3e-05 |
| African/African American2 / 74,912 | 2.7e-05 |
| European (non-Finnish)17 / 1,179,872 | 1.4e-05 |
0 alternate alleles recorded in 6 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern.
gnomAD v2.1
AF 4e-06 · 1 / 251,340 alleles · 0 hom
| Ashkenazi Jewish1 / 10,080 | 9.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.42549e-05; MAF= 0.00143%, 23/1613478 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37883e-05; MAF= 0.00338%, 1/29596 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97867e-06; MAF= 0.00040%, 1/251340 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.885
- BayesDel
- 0.301
How the predictions were used
PP3 SupportingREVEL score of 0.885 meets the VCEP threshold of ≥0.7 for missense variants. SpliceAI predicts no splicing impact (max delta 0.00), and the variant is not in a splicing-relevant context. BayesDel score is 0.301 (intermediate). Details ▾Hide ▴
Evidence considered
- REVEL = 0.885 (≥0.7 threshold met)
- SpliceAI max delta = 0.00 (no splice impact)
- BayesDel = 0.301
Sources
BP4 REVEL score of 0.885 exceeds the VCEP BP4 threshold of ≤0.3, indicating computational evidence does not support a benign interpretation. SpliceAI predicts no splicing impact (max delta 0.00). Details ▾Hide ▴
Evidence considered
- REVEL = 0.885 (exceeds ≤0.3 threshold)
- SpliceAI max delta = 0.00
Sources
revelspliceai ↗
BP7 N/ANM_004333.5:c.1661T>C is a missense variant (p.Ile554Thr), not a synonymous variant. BP7 applies only to synonymous variants and intronic/non-coding variants outside canonical splice sites. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies only to synonymous and non-coding variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.885. BayesDel score = 0.301041.
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 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 2015 standards and guidelines for variant interpretation. It describes the general classification framework and does not discuss NM_004333.5:c.1661T>C or any BRAF variant.Does not name this variant
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PMID 20301680 ↗HRAS-Related Costello Syndrome.Adam MP et al. · 1993GeneReviews entry on HRAS-related Costello syndrome. Discusses HRAS mutations and RASopathy phenotypes at the gene level. NM_004333.5:c.1661T>C (BRAF) was not identified in the abstract or available metadata.Does not name this variant
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PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Authors/Task Force members et al. · 20142014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. General cardiology guidelines that do not discuss BRAF variants or RASopathies in variant-specific detail.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
23 / 1,613,478 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Likely benign · 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/variation/239870/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140476745-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140776945-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-140776945-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004333.5%3Ac.1661…
- OncoKB ↗www.oncokb.org/gene/BRAF/I554T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=221441291
- 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= 1.42549e-05; MAF= 0.00143%, 23/1613478 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37883e-05; MAF= 0.00338%, 1/29596 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97867e-06; MAF= 0.00040%, 1/251340 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92063e-05; MAF= 0.00992%, 1/10080 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 239870)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.885. BayesDel score = 0.301041.
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; COSV56430604, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.