About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.770A>G, p.(Gln257Arg)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
VCEP-approved functional studies show abnormal effects in more than one approved assay for this variant. Q257R is listed as pathogenic in MEK activation, ERK activation, and BRAF kinase activity assays, supporting a damaging gain-of-function effect.
PM1Moderate
PM1 · moderate
This missense variant is located in exon 6, and the RASopathy expert panel explicitly permits PM1 at moderate strength for variants in exon 6 as a critical and well-established functional region.
PP3Supporting
PP3 · supporting
Computational evidence supports a damaging effect. REVEL is 0.838, which is above the PP3 threshold of 0.7, BayesDel is positive at 0.476355, and SpliceAI shows only a low predicted splice effect with a maximum delta score of 0.21, supporting interpretation primarily as a deleterious missense change.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
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: PP5 supporting, PM1 moderate, PP3 supporting, PS3 moderate; 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 / 1,613,978 alleles
gnomAD v4.1: 1 / 1,613,978 alleles. Recorded AF 6.19587e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 4 met · 4 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BRAF c.770A>G (p.Gln257Arg) variant has been reported in ClinVar as pathogenic, including expert panel review.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,613,978 alleles; AF 0.00006%), which is below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.
In VCEP-approved functional studies, Q257R showed abnormal results in MEK activation, ERK activation, and BRAF kinase activity assays, consistent with a damaging gain-of-function effect.
Computational evidence supports a deleterious missense effect, with REVEL 0.838 above the PP3 threshold of 0.7, a positive BayesDel score of 0.476355, and SpliceAI showing only a low predicted splice effect with a maximum delta score of 0.21.
No criteria match.
Met · 4
PS3 ModerateVCEP-approved functional studies show abnormal effects in more than one approved assay for this variant. Q257R is listed as pathogenic in MEK activation, ERK activation, and BRAF kinase activity assays, supporting a damaging gain-of-function effect. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- Approved functional studies summary lists BRAF Q257R as pathogenic in MEK activation assay.
- Approved functional studies summary lists BRAF Q257R as pathogenic in ERK activation assay.
- Approved functional studies summary lists BRAF Q257R as pathogenic in BRAF kinase activity assay.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:16439621 ↗PMID:16474404 ↗PMID:19376813 ↗PMID:33019809 ↗
PM1 ModerateThis missense variant is located in exon 6, and the RASopathy expert panel explicitly permits PM1 at moderate strength for variants in exon 6 as a critical and well-established functional region. Details ▾Hide ▴
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]).
Evidence considered
- Variant maps to exon 6.
- RASopathy VCEP PM1 includes exon 6 as an eligible region.
Sources
PP3 SupportingComputational evidence supports a damaging effect. REVEL is 0.838, which is above the PP3 threshold of 0.7, BayesDel is positive at 0.476355, and SpliceAI shows only a low predicted splice effect with a maximum delta score of 0.21, supporting interpretation primarily as a deleterious missense change. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.838 exceeds the PP3 threshold of 0.7.
- BayesDel score 0.476355 is in the damaging direction.
- SpliceAI max delta score 0.21 does not provide stronger splice-based evidence than the missense prediction.
Sources
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,613,978 alleles (AF 6.195871319187746e-07; 0.00006%), so it is not absent from controls and does not meet this VCEP PM2 rule. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 at AF 6.195871319187746e-07 (1/1
- 613
- 978 alleles)
- with no homozygotes.
Sources
BA1 Population frequency is well below the BA1 threshold. The highest observed frequency is 0.00008%, which is below the BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >=0.05%.
Evidence considered
- Highest observed subpopulation AF 0.00008% (European non-Finnish).
Sources
BS1 Population frequency is far below the BS1 threshold. The highest observed frequency is 0.00008% in the European non-Finnish population, which is below the BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v4.1 total AF 0.00006%.
- Highest observed subpopulation AF 0.00008% (European non-Finnish).
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.838, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.476355. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.838.
- BayesDel 0.476355.
- SpliceAI max delta score 0.21.
Sources
Not assessed · 11 · no assessment recorded
PS1 The reviewed evidence did not establish a previously classified pathogenic variant producing the same amino acid change through a different nucleotide change, so this criterion cannot be confirmed from the current record. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- No alternate nucleotide change causing the same amino acid substitution was confirmed in the reviewed evidence.
Still missing
- A search for an alternate nucleotide change causing p.Gln257Arg with established pathogenicity is needed.
Sources
PS2 Published reports associated with this variant and cardio-facio-cutaneous syndrome were identified, but the reviewed evidence did not document confirmed maternity and paternity for an exact-variant de novo occurrence, so this criterion cannot be assigned at this time. Details ▾Hide ▴
Rule
Point-based de novo scoring; 4 points = Very Strong, 2 points = Strong, 1 point = Moderate.
Evidence considered
- RASopathy VCEP PS2 uses a point-based de novo framework.
- Literature triage identified early CFC reports as potentially relevant
- but de novo confirmation details were not established in the reviewed evidence.
Still missing
- Patient-level confirmation of de novo status with maternity and paternity testing is needed.
- Independent exact-variant de novo case counting is needed under the RASopathy point system.
Sources
PS4 This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but the reviewed evidence did not establish the exact number of independent affected probands needed to score the RASopathy PS4 point framework. Details ▾Hide ▴
Rule
>=5 points = Strong; >=3 points = Moderate; >=1 point = Supporting.
Evidence considered
- ClinVar contains pathogenic submissions including expert panel review.
- Early cardio-facio-cutaneous syndrome publications were identified as potentially relevant to exact-variant case counts.
Still missing
- Deduplicated exact-variant case counts are needed.
- Patient-level evidence is needed to assign the appropriate PS4 point total.
Sources
PM5 Available evidence does not establish a different pathogenic or likely pathogenic missense change at codon 257 in BRAF or RAF1, so this codon-based criterion cannot be confirmed from the reviewed evidence. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon (Moderate); >=2 different [likely] pathogenic residue changes at the same codon observed in >=5 probands (Strong).
Evidence considered
- RASopathy VCEP PM5 requires a previously established pathogenic missense change at the same codon
- the reviewed evidence did not confirm such a substitution for codon 257.
Still missing
- A codon-specific review of reported pathogenic substitutions at BRAF/RAF1 codon 257 is still needed.
Sources
PM6 Published reports suggest this variant has been observed in affected individuals, but the reviewed evidence did not provide sufficient patient-level documentation to score an assumed de novo occurrence under the RASopathy point framework. Details ▾Hide ▴
Rule
2 points = Strong; 1 point = Moderate; 0.5 points = Supporting.
Evidence considered
- Literature triage identified potential de novo reports
- but exact scoring details were not established in the reviewed evidence.
Still missing
- Exact-variant reports with parental testing details are needed.
- Independent case counting under the VCEP point system is needed.
Sources
PP1 No informative meioses showing segregation with disease were identified for this variant. Details ▾Hide ▴
Rule
>=3 informative meioses = Supporting; >=5 = Moderate; >=7 = Strong.
Evidence considered
- No segregation dataset was established in the reviewed evidence.
Still missing
- Family segregation data with informative meiosis counts are needed.
Sources
PP2 This criterion requires a BRAF missense constraint metric above the specified threshold, but the reviewed evidence did not provide the gene-level missense z score needed to confirm the rule. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- RASopathy VCEP PP2 requires missense z score >3.09 in gnomAD.
Still missing
- BRAF missense z score from gnomAD or another accepted source is needed to assess this criterion.
Sources
BS2 No evidence was identified that this variant is observed in healthy individuals in a manner that satisfies the RASopathy point-based BS2 specification. Details ▾Hide ▴
Rule
-4 points = Strong; -1 point = Supporting.
Evidence considered
- gnomAD shows one allele and no homozygotes
- which does not by itself satisfy the BS2 framework.
Still missing
- Validated unaffected carrier data meeting the VCEP point framework would be needed.
Sources
BS4 No family data showing lack of segregation were identified for this variant. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No non-segregation evidence was established in the reviewed materials.
Still missing
- Pedigree-level segregation data would be needed to assess this criterion.
Sources
BP2 No evidence was identified that this variant occurs with an alternative molecular diagnosis in cis or trans in a way that supports this criterion. Details ▾Hide ▴
Rule
Point-based benign evidence for an alternative molecular cause in the same gene and/or with BP5.
Evidence considered
- No qualifying alternate molecular diagnosis or phase information was identified in the reviewed evidence.
Still missing
- Case-level molecular findings and phase information would be needed.
Sources
BP5 No alternate molecular explanation for the phenotype was identified in the reviewed evidence. Details ▾Hide ▴
Rule
Point-based benign evidence for an alternative molecular cause in a different gene and/or phenotype fully explained by another variant.
Evidence considered
- No qualifying alternate molecular diagnosis was established.
Still missing
- Case-level data demonstrating a different causal variant would be needed.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution and does not fall within the null-variant categories used for PVS1 assessment. Details ▾Hide ▴
Evidence considered
- PVS1 is marked not applicable in the RASopathy VCEP framework.
- Generic PVS1 scaffold states this variant is not a nonsense
- frameshift
- or canonical +/-1
- 2 splice variant.
Sources
PM3 N/AThis criterion is for recessive disorders and is not applicable in this framework. Details ▾Hide ▴
PM4 N/AThis is a missense substitution and does not change protein length, so this criterion for in-frame length changes or stop-loss variants does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is a missense substitution.
Sources
PP4 N/AThis expert panel framework does not apply PP4 for this condition because phenotype specificity is addressed through PS4-based specifications. Details ▾Hide ▴
Rule
Not applicable, see PS4.
Evidence considered
- RASopathy VCEP marks PP4 as not applicable.
Sources
BS3 N/AThis expert panel framework does not apply BS3 for this gene specification. Details ▾Hide ▴
BP1 N/AThis is a missense variant, whereas this criterion is specified here for truncating loss-of-function variants in a gain-of-function disease context. Details ▾Hide ▴
Rule
Use for truncating loss-of-function variants in genes without established loss-of-function disease correlation in RASopathies.
Evidence considered
- Variant is missense p.(Gln257Arg)/p.(Q257R).
Sources
BP3 N/AThis criterion is not applicable in this expert panel framework. Details ▾Hide ▴
BP6 N/AThis criterion is not used by this expert panel framework. Details ▾Hide ▴
Rule
Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- RASopathy VCEP marks BP6 as not applicable.
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so this criterion does not apply. Details ▾Hide ▴
Rule
Applicable to synonymous, certain intronic, or non-coding variants with no predicted splice impact and low conservation concern.
Evidence considered
- Variant is missense p.(Gln257Arg).
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.770A>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Gln257Arg)
- GRCh38
- chr7:140801502 T>C
- GRCh37
- chr7:140501302 T>C
Gene diagram
Every interpreted variant in BRAF, mapped onto the exon structure of NM_001354609.1. Select a row to find it on the plot.
BRAFNM_001354609.1
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRAF
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,978 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,978 alleles · 0 hom
| European (non-Finnish)1 / 1,179,918 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19587e-07; MAF= 0.00006%, 1/1613978 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47517e-07; MAF= 0.00008%, 1/1179918 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational evidence supports a damaging effect. REVEL is 0.838, which is above the PP3 threshold of 0.7, BayesDel is positive at 0.476355, and SpliceAI shows only a low predicted splice effect with a maximum delta score of 0.21, supporting interpretation primarily as a deleterious missense change. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.838 exceeds the PP3 threshold of 0.7.
- BayesDel score 0.476355 is in the damaging direction.
- SpliceAI max delta score 0.21 does not provide stronger splice-based evidence than the missense prediction.
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.838, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.476355. Details ▾Hide ▴
Rule
For missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.838.
- BayesDel 0.476355.
- SpliceAI max delta score 0.21.
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so this criterion does not apply. Details ▾Hide ▴
Rule
Applicable to synonymous, certain intronic, or non-coding variants with no predicted splice impact and low conservation concern.
Evidence considered
- Variant is missense p.(Gln257Arg).
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21). REVEL score = 0.838. BayesDel score = 0.476355.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,978 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/13973/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501302-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801502-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/Q257R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.770A%3EG
- 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= 6.19587e-07; MAF= 0.00006%, 1/1613978 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47517e-07; MAF= 0.00008%, 1/1179918 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (32 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21). REVEL score = 0.838. BayesDel score = 0.476355.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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.