About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.708C>T, p.(Asn236=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
Population frequency exceeds the RASopathy VCEP BA1 threshold of 0.05%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.05% threshold.
BS1Strong
BS1 · strong
Population frequency exceeds the RASopathy VCEP BS1 threshold of 0.025%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.025% threshold.
BP4Supporting
BP4 · supporting
Computational evidence supports no meaningful effect. This synonymous variant has no applicable REVEL score, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is consistent with negligible splicing effect.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting benign; maps to Benign.
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
217 / 1,606,934 alleles
gnomAD v4.1: 217 / 1,606,934 alleles. Recorded AF 0.00013504. Recorded homozygote count 2.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255343; MAF= 0.02553%, 72/281974 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00176783; MAF= 0.17678%, 54/30546 alleles, homozygotes = 1); grpmax FAF= 0.00139101.
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 curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
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 · 3 not met · 10 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
The BRAF c.708C>T (p.Asn236=) variant has been reported in ClinVar as benign, including a benign expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is present in population databases above the BRAF RASopathy VCEP BA1 threshold of 0.05%, with a grpmax filtering allele frequency of 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1; the highest observed population frequency is in South Asian individuals at 0.17678% in gnomAD v2.1 and 0.14861% in gnomAD v4.1.
This is a synonymous variant, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.06, supporting no meaningful impact on splicing.
No criteria match.
Met · 4
BA1 Stand alonePopulation frequency exceeds the RASopathy VCEP BA1 threshold of 0.05%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.05% threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00139101 (0.13910%).
- gnomAD v4.1 grpmax FAF 0.0012819 (0.12819%).
Sources
BS1 StrongPopulation frequency exceeds the RASopathy VCEP BS1 threshold of 0.025%. The highest filtering allele frequency is 0.13910% in gnomAD v2.1 and 0.12819% in gnomAD v4.1, both above the 0.025% threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00139101 (0.13910%).
- gnomAD v4.1 grpmax FAF 0.0012819 (0.12819%).
Sources
BP4 SupportingComputational evidence supports no meaningful effect. This synonymous variant has no applicable REVEL score, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is consistent with negligible splicing effect. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06.
- Variant is synonymous.
Sources
BP6 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign. Details ▾Hide ▴
Not met · 3 · evaluated, threshold not reached
PM1 This variant is in exon 5 at codon 236, which is outside the BRAF RASopathy VCEP PM1 regions limited to exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627). Details ▾Hide ▴
Rule
Applicable only to exon 6, exon 11, P-loop (AA 459-474), and CR3 activation segment (AA 594-627).
Evidence considered
- Variant maps to exon 5 and p.(Asn236=).
- Cancer Hotspots review did not identify a hotspot row for residue N236.
Sources
PM2 This variant is present in gnomAD, so it does not meet the PM2 requirement for absence from controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.02553% (72/281974 alleles).
- gnomAD v4.1 total AF 0.01350% (217/1606934 alleles).
Sources
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and no applicable missense predictor result was identified for this synonymous variant. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06.
- REVEL was not available and is not the relevant primary predictor for this synonymous change.
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
PS3 No approved functional study for this exact variant was identified, so PS3 cannot be applied. Details ▾Hide ▴
Rule
PS3 Supporting requires one approved assay; PS3 Moderate requires two or more different approved assays.
Evidence considered
- The approved functional-study summary lists validation assays but no result for this exact variant.
- OncoKB did not provide variant-specific functional evidence.
Still missing
- No variant-specific approved functional assay result was identified.
Sources
PS4 No case-enrichment or point-based affected-individual evidence was identified for this variant, and the variant is not absent from population databases, so PS4 cannot be applied. Details ▾Hide ▴
Rule
PS4 uses the RASopathy VCEP point-based framework.
Evidence considered
- ClinVar shows benign/likely benign submissions including an expert-panel benign classification.
- The variant is present in gnomAD and therefore does not meet the PM2 prerequisite for PS4 use in this framework.
Still missing
- No exact-variant affected-case count meeting the VCEP point system was identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant, so PM6 cannot be applied from the available evidence. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
BS2 Population observations were identified, including rare homozygotes in gnomAD, but no phenotype-confirmed unaffected-case evidence was identified to score BS2 under the RASopathy VCEP point system. Details ▾Hide ▴
Rule
BS2 uses the RASopathy VCEP point-based framework.
Evidence considered
- gnomAD v2.1 includes 1 homozygote.
- gnomAD v4.1 includes 2 homozygotes.
Still missing
- No phenotype-confirmed unaffected observations were identified.
Sources
BS4 No informative non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No evidence of an alternative molecular cause in the same gene or phasing information relevant to BP2 was identified. Details ▾Hide ▴
Rule
BP2 uses the RASopathy VCEP negative-point framework.
Evidence considered
- No BP2-relevant case-level molecular data were identified.
Still missing
- No same-gene alternative molecular diagnosis or phase data were identified.
Sources
BP5 No alternative molecular diagnosis in a different gene or phenotype explanation relevant to BP5 was identified. Details ▾Hide ▴
Rule
BP5 uses the RASopathy VCEP negative-point framework.
Evidence considered
- No BP5-relevant alternate diagnosis evidence was identified.
Still missing
- No alternative molecular cause was identified.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but the available evidence reviewed here did not establish whether the altered nucleotide is not highly conserved, so BP7 was not fully assessed. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Variant is synonymous.
- SpliceAI max delta score 0.06.
Still missing
- No conservation evidence for the altered nucleotide was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a synonymous variant, not a nonsense, frameshift, or canonical +/-1 or 2 splice variant, so PVS1 does not apply. Details ▾Hide ▴
Rule
PVS1 not applicable for this variant type.
Evidence considered
- Protein consequence is p.(Asn236=)/p.(N236=).
- Generic PVS1 scaffold states this variant is outside default null-variant PVS1 categories.
- The BRAF RASopathy framework marks PVS1 as not applicable for this case.
Sources
PS1 N/AThis variant does not change the amino acid sequence, so the same-amino-acid pathogenic-variant rule does not apply. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- Variant is synonymous: p.(Asn236=)/p.(N236=).
- PS1 in this framework is for the same amino acid change as an established pathogenic variant.
Sources
PM3 N/APM3 is not applicable in this RASopathy BRAF framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- The BRAF RASopathy VCEP marks PM3 as not applicable.
Sources
PM4 N/AThis is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 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 type is synonymous substitution.
Sources
PM5 N/AThis variant does not create a novel missense change at codon 236, so PM5 does not apply. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
- Variant is synonymous and does not alter the amino acid.
Sources
PP2 N/APP2 is a missense-based rule, and this variant is synonymous. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- Variant is p.(Asn236=)/p.(N236=).
Sources
PP4 N/APP4 is not applicable in this RASopathy BRAF framework. Details ▾Hide ▴
Rule
Not applicable, see PS4.
Evidence considered
- The BRAF RASopathy VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not used in this framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- The BRAF RASopathy VCEP marks PP5 as not applicable.
Sources
BS3 N/ABS3 is not applicable in this RASopathy BRAF framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- The BRAF RASopathy VCEP marks BS3 as not applicable.
Sources
BP1 N/ABP1 in this RASopathy framework is for truncating loss-of-function variants in genes without an established loss-of-function disease correlation, and this variant is a synonymous substitution. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease.
Evidence considered
- Variant type is synonymous substitution.
Sources
BP3 N/ABP3 is not applicable in this RASopathy BRAF framework. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- The BRAF RASopathy VCEP marks BP3 as not applicable.
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.708C>T
- Protein (HGVS p.)
- NP_001341538.1:p.(Asn236=)
- GRCh38
- chr7:140807963 G>A
- GRCh37
- chr7:140507763 G>A
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
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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
217 / 1,606,934 alleles
AF 0.000135 · 2 homozygotes · FAF 0.00128
gnomAD v2.1
72 / 281,974 alleles
AF 0.000255 · 1 homozygotes · FAF 0.00139
By genetic ancestry
gnomAD v4.1
AF 0.00014 · 217 / 1,606,934 alleles · 2 hom · FAF 0.0013
| South Asian135 / 90,840 | 0.00152 hom |
| Middle Eastern6 / 6,046 | 0.00099 |
| Remaining individuals25 / 62,274 | 0.0004 |
| East Asian3 / 44,768 | 6.7e-05 |
| African/African American4 / 74,766 | 5.4e-05 |
| European (non-Finnish)41 / 1,174,086 | 3.5e-05 |
| Ashkenazi Jewish1 / 29,546 | 3.4e-05 |
| Admixed American2 / 59,950 | 3.3e-05 |
0 alternate alleles recorded in 2 other groups: European (Finnish), Amish.
gnomAD v2.1
AF 0.00026 · 72 / 281,974 alleles · 1 hom · FAF 0.0014
| South Asian54 / 30,546 | 0.00181 hom |
| East Asian3 / 19,940 | 0.00015 |
| Remaining individuals1 / 7,190 | 0.00014 |
| Ashkenazi Jewish1 / 10,356 | 9.7e-05 |
| European (non-Finnish)12 / 128,658 | 9.3e-05 |
| Admixed American1 / 35,354 | 2.8e-05 |
0 alternate alleles recorded in 2 other groups: African/African American, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00013504; MAF= 0.01350%, 217/1606934 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00148613; MAF= 0.14861%, 135/90840 alleles, homozygotes = 2); grpmax FAF= 0.0012819.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255343; MAF= 0.02553%, 72/281974 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00176783; MAF= 0.17678%, 54/30546 alleles, homozygotes = 1); grpmax FAF= 0.00139101.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingComputational evidence supports no meaningful effect. This synonymous variant has no applicable REVEL score, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, which is consistent with negligible splicing effect. Details ▾Hide ▴
Rule
For splicing variants: predicted outcome is negligible or does not match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06.
- Variant is synonymous.
Sources
PP3 Computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.06, and no applicable missense predictor result was identified for this synonymous variant. Details ▾Hide ▴
Rule
For missense variants: REVEL >=0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.06.
- REVEL was not available and is not the relevant primary predictor for this synonymous change.
Sources
BP7 This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but the available evidence reviewed here did not establish whether the altered nucleotide is not highly conserved, so BP7 was not fully assessed. Details ▾Hide ▴
Rule
A synonymous variant with no predicted splice impact and a nucleotide that is not highly conserved.
Evidence considered
- Variant is synonymous.
- SpliceAI max delta score 0.06.
Still missing
- No conservation evidence for the altered nucleotide was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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
217 / 1,606,934 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/44827/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140507763-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140807963-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/N236=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.708C%3ET
- 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= 0.00013504; MAF= 0.01350%, 217/1606934 alleles, homozygotes = 2) and has highest observed frequency in the South Asian population (AF= 0.00148613; MAF= 0.14861%, 135/90840 alleles, homozygotes = 2); grpmax FAF= 0.0012819.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255343; MAF= 0.02553%, 72/281974 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00176783; MAF= 0.17678%, 54/30546 alleles, homozygotes = 1); grpmax FAF= 0.00139101.
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.