About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1595G>A, p.(Cys532Tyr)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy VCEP requirement that PM2 be applied at supporting strength when the variant is absent from population controls.
PP3Supporting
PP3 · supporting
For this missense variant, the REVEL score is 0.912, which is above the RASopathy VCEP PP3 threshold of 0.7 and supports a deleterious protein effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice mechanism, and the BayesDel score is 0.376689, which is directionally supportive of a damaging effect.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely 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: PM2 supporting, PP3 supporting, PP5 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.
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 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
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: 3 met · 4 not met · 12 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.1595G>A (p.Cys532Tyr, p.C532Y) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at supporting strength under the RASopathy VCEP framework.
Approved RASopathy VCEP functional assay frameworks are available, but no variant-specific approved functional study result for p.(Cys532Tyr) was identified, so PS3 was not applied.
Computational evidence supports a deleterious effect because REVEL is 0.912, above the VCEP PP3 threshold of 0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.00 and BayesDel is 0.376689; these findings support PP3 and do not support BP4.
This missense change does not meet PM1 because the RASopathy VCEP limits PM1 in BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627), and codon 532 is outside the specified amino acid regions.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy VCEP requirement that PM2 be applied at supporting strength when the variant is absent from population controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP3 SupportingFor this missense variant, the REVEL score is 0.912, which is above the RASopathy VCEP PP3 threshold of 0.7 and supports a deleterious protein effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice mechanism, and the BayesDel score is 0.376689, which is directionally supportive of a damaging effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.912
- SpliceAI max delta score 0.00
- BayesDel 0.376689
Sources
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PM1 The RASopathy VCEP restricts PM1 for BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627). This variant affects codon 532, which is outside the specified amino acid regions, so PM1 is not met. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]).
Evidence considered
- Variant protein consequence is p.(Cys532Tyr) at codon 532
- VCEP PM1 regions are limited to exon 6
- exon 11
- P-loop 459-474
- and CR3 activation segment 594-627
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 stand-alone threshold of 0.05%, so BA1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025%, so BS1 is not met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 For this missense variant, the REVEL score is 0.912, which is above the benign BP4 threshold of 0.3, so BP4 is not met. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.912
- SpliceAI max delta score 0.00
Sources
Not assessed · 12 · no assessment recorded
PS1 No verified evidence was identified showing a different nucleotide change causing the same amino acid substitution as an established pathogenic variant in BRAF or the analogous RAF1 residue, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change; applicable for analogous residue positions in BRAF and RAF1.
Evidence considered
- VCEP PS1 allows the same amino acid change
- including analogous residue positions in BRAF and RAF1
Still missing
- Need a verified pathogenic same-amino-acid match in BRAF or the analogous RAF1 residue under the VCEP rule.
Sources
PS2 No case-level evidence was identified confirming this variant occurred de novo with confirmed maternity and paternity in an affected individual, so PS2 was not assessed. Details ▾Hide ▴
Rule
Point-based de novo scoring: 4 points Very Strong, 2 points Strong, 1 point Moderate.
Evidence considered
- VCEP point-based de novo framework is available
- Current materials do not provide confirmatory de novo details for this variant
Still missing
- Need published or curated de novo case data with confirmed parentage and sufficient phenotype specificity for point assignment.
Sources
PS3 RASopathy VCEP-approved functional assay frameworks are available, but no variant-specific approved assay result for p.(Cys532Tyr) was identified in the reviewed materials, so PS3 was not applied. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- Approved assay list includes MEK activation
- ERK activation
- and BRAF kinase activity
- No variant-specific reviewed functional evidence was identified for C532Y in the retrieved materials
Still missing
- Need at least one approved variant-specific functional assay result for PS3_Supporting or two different approved assays for PS3_Moderate.
Sources
PS4 This variant is reported in ClinVar, but no verified count of unrelated affected individuals or point-based case enrichment data was identified for this variant, so PS4 was not assessed. Details ▾Hide ▴
Rule
Point-based case enrichment: at least 5 points Strong, 3 points Moderate, 1 point Supporting.
Evidence considered
- ClinVar lists the variant as Likely pathogenic including expert panel review
- No PS4 point total was available in the reviewed materials
Still missing
- Need case counts or point-based affected-individual evidence meeting the RASopathy VCEP PS4 thresholds.
Sources
PM5 No verified same-codon pathogenic missense comparator was identified for this residue in the reviewed materials, so PM5 was not assessed. Details ▾Hide ▴
Rule
One pathogenic/likely pathogenic residue change at the same codon = Moderate; at least two different pathogenic/likely pathogenic residue changes at the same codon observed in at least five probands = Strong.
Evidence considered
- VCEP provides same-codon PM5 rules
- Current materials did not verify a same-codon comparator for codon 532
Still missing
- Need evidence for one pathogenic or likely pathogenic missense change at the same codon for Moderate strength
- or at least two different pathogenic/likely pathogenic same-codon changes observed in at least five probands for Strong strength.
Sources
PM6 No case-level evidence was identified showing this variant was assumed de novo without full parental confirmation, so PM6 was not assessed. Details ▾Hide ▴
Rule
Point-based assumed de novo scoring: 2 points Strong, 1 point Moderate, 0.5 point Supporting.
Evidence considered
- VCEP point-based PM6 framework is available
- No usable assumed de novo evidence was identified for this variant
Still missing
- Need case-level assumed de novo evidence and phenotype details sufficient for VCEP point assignment.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
At least 3 informative meioses = Supporting; at least 5 = Moderate; at least 7 = Strong.
Evidence considered
- VCEP PP1 requires informative meioses
- No family segregation data were identified
Still missing
- Need informative meioses showing co-segregation in affected relatives.
Sources
PP2 This is a missense variant in BRAF, but no gnomAD missense z score was provided in the reviewed materials to verify that the VCEP threshold of greater than 3.09 is met, so PP2 was not assessed. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- VCEP PP2 threshold is missense z score >3.09
Still missing
- Need the BRAF missense z score used by the VCEP rule.
Sources
BS2 No evidence was identified showing this variant in unaffected adult individuals under the VCEP point-based BS2 framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
Point-based BS2 scoring for healthy individuals.
Evidence considered
- VCEP uses point-based BS2 scoring
- No unaffected-carrier data were identified
Still missing
- Need qualifying unaffected-carrier evidence with enough detail for VCEP point assignment.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- VCEP BS4 requires one informative meiosis
- No non-segregation evidence was identified
Still missing
- Need an informative meiosis showing non-segregation in an affected family context.
Sources
BP2 No evidence was identified that this variant occurred with an alternative molecular explanation in the same gene, so BP2 was not assessed. Details ▾Hide ▴
Rule
Point-based BP2 scoring: at least -1 point Supporting, at least -2 points Moderate, at least -4 points Strong.
Evidence considered
- VCEP BP2 uses point-based scoring for alternative same-gene molecular explanations
- No such evidence was identified
Still missing
- Need same-gene alternative molecular cause evidence with sufficient phenotype context for point assignment.
Sources
BP5 No evidence was identified for an alternative molecular explanation in a different gene or for a phenotype fully explained by another variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
Point-based BP5 scoring: at least -1 point Supporting, at least -2 points Moderate, at least -4 points Strong.
Evidence considered
- VCEP BP5 uses point-based scoring for alternate molecular explanations
- No such evidence was identified
Still missing
- Need alternative-diagnosis molecular evidence with phenotype context for VCEP point assignment.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a null variant, and the variant-level PVS1 assessment states that it does not fall within the generic PVS1 buckets for nonsense, frameshift, or canonical splice-site changes; therefore PVS1 is not applicable. Details ▾Hide ▴
Rule
PVS1 not applicable for this variant type.
Evidence considered
- NP_001341538.1:p.(Cys532Tyr) is a missense change
- Generic PVS1 scaffold says the variant is outside null-variant buckets
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/APM3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant consequence is p.(Cys532Tyr) missense
Sources
PP4 N/APP4 is not applicable in this RASopathy VCEP framework, which directs phenotype-weighted case evidence to PS4 instead. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BP1 N/AThis criterion is reserved here for truncating variants in genes where gain-of-function missense changes are the primary disease mechanism. Because this variant is missense, BP1 is not applicable. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease in this RASopathy framework.
Evidence considered
- Variant consequence is missense
- VCEP BP1 use is directed to truncating variants
Sources
BP3 N/ABP3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- VCEP marks BP6 as not applicable
Sources
BP7 N/AThis is a missense variant rather than a synonymous or relevant noncoding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applicable to synonymous, intronic, or non-coding variants with no predicted splice impact and no high conservation concern.
Evidence considered
- Variant consequence is missense
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1595G>A
- Protein (HGVS p.)
- NP_001341538.1:p.(Cys532Tyr)
- GRCh38
- chr7:140777011 C>T
- GRCh37
- chr7:140476811 C>T
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingFor this missense variant, the REVEL score is 0.912, which is above the RASopathy VCEP PP3 threshold of 0.7 and supports a deleterious protein effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice mechanism, and the BayesDel score is 0.376689, which is directionally supportive of a damaging effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.912
- SpliceAI max delta score 0.00
- BayesDel 0.376689
Sources
BP4 For this missense variant, the REVEL score is 0.912, which is above the benign BP4 threshold of 0.3, so BP4 is not met. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.912
- SpliceAI max delta score 0.00
Sources
BP7 N/AThis is a missense variant rather than a synonymous or relevant noncoding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Applicable to synonymous, intronic, or non-coding variants with no predicted splice impact and no high conservation concern.
Evidence considered
- Variant consequence is missense
- SpliceAI max delta score 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.912. BayesDel score = 0.376689.
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
Captured gnomAD v4.1 source record
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/40380/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140476811-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140777011-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/C532Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.1595G%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.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.912. BayesDel score = 0.376689.
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.