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BRAFc.1799T>GLikely pathogenic
Print report
Variant interpretation report

BRAF c.1799T>G, p.(Val600Gly)

NM_001354609.1:c.1799T>G NP_001341538.1:p.(Val600Gly) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BRAF

No gene-level summary was recorded for this case.

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: 6 Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Supporting
PS3 · supporting

In a published functional study, this variant increased ERK and ELK phosphorylation compared with wild type, consistent with an activating effect. Under the BRAF RASopathy specification, one approved functional assay supports PS3 at supporting strength.

PM1Moderate
PM1 · moderate

This missense change affects codon 600 within the BRAF CR3 activation segment (amino acids 594-627), a critical functional domain specified by the RASopathy framework. Published structural-functional data also support the importance of the activation segment in BRAF activation.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy PM2 requirement that the variant be absent from controls.

PM5Moderate
PM5 · moderate

Other missense substitutions affecting the same codon have been reported in ClinVar as likely pathogenic or pathogenic, including p.Val600Leu and p.Val600Met. This satisfies the BRAF same-residue comparator rule for PM5 at moderate strength.

PP3Supporting
PP3 · supporting

Computational evidence supports a damaging missense effect. REVEL is 0.925, which is above the RASopathy PP3 threshold of 0.7; BayesDel is 0.357299; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, which is consistent with this being primarily a missense effect rather than a splice-altering variant.

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: Likely pathogenic

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 Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.110 maximum delta

Recorded SpliceAI maximum delta score: 0.110. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
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.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
27 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV56080151, n = 27 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
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: 6 met · 3 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The BRAF c.1799T>G (p.Val600Gly, p.V600G) variant has been observed in somatic cancers, including 27 occurrences in COSMIC, and has been reported in ClinVar with a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population reference datasets.

In a published functional study, p.Val600Gly increased ERK and ELK phosphorylation relative to wild type, consistent with an activating effect; the BRAF RASopathy functional-study framework supports PS3 at supporting strength when one approved assay is available.

Computational evidence supports a damaging missense effect, with REVEL 0.925 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.357299, and SpliceAI showing no major splice effect with a maximum delta score of 0.11.

Met · 6

PS3 SupportingIn a published functional study, this variant increased ERK and ELK phosphorylation compared with wild type, consistent with an activating effect. Under the BRAF RASopathy specification, one approved functional assay supports PS3 at supporting strength. Details ▾Hide ▴
Rule
One approved assay.
Evidence considered
  • PMID 20735442 functional analysis showed increased ERK and ELK phosphorylation versus wild type
  • RASopathy approved functional assay framework
Sources
PMID:20735442 ↗cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM1 ModerateThis missense change affects codon 600 within the BRAF CR3 activation segment (amino acids 594-627), a critical functional domain specified by the RASopathy framework. Published structural-functional data also support the importance of the activation segment in BRAF activation. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains, including the CR3 activation segment (AA 594-627).
Evidence considered
  • Codon 600 lies within the CSPEC-listed CR3 activation segment AA 594-627
  • Published BRAF activation-segment mechanism data
Sources
cspec ↗PMID:15035987 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy PM2 requirement that the variant be absent from 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
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 ModerateOther missense substitutions affecting the same codon have been reported in ClinVar as likely pathogenic or pathogenic, including p.Val600Leu and p.Val600Met. This satisfies the BRAF same-residue comparator rule for PM5 at moderate strength. Details ▾Hide ▴
Rule
1 pathogenic or likely pathogenic residue change at the same codon.
Evidence considered
  • ClinVar same-codon pathogenic/likely pathogenic comparators at Val600
  • CSPEC PM5 same-residue rule
Sources
cspec ↗clinvar ↗
PP3 SupportingComputational evidence supports a damaging missense effect. REVEL is 0.925, which is above the RASopathy PP3 threshold of 0.7; BayesDel is 0.357299; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, which is consistent with this being primarily a missense effect rather than a splice-altering variant. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7.
Evidence considered
  • REVEL 0.925
  • BayesDel 0.357299
  • SpliceAI max delta 0.11
Sources
cspec ↗revelbayesdelspliceai ↗
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Rule
Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • CSPEC marks PP5 not applicable
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 3 · evaluated, threshold not reached

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BA1 threshold of at least 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BS1 threshold of at least 0.025%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 Available computational evidence does not support BP4. REVEL is 0.925, which is above the benign BP4 threshold of 0.3, and BayesDel is 0.357299; although SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, the missense predictor result does not support a benign interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
  • REVEL 0.925
  • BayesDel 0.357299
  • SpliceAI max delta 0.11
Sources
cspec ↗revelbayesdelspliceai ↗

Not assessed · 9 · no assessment recorded

PS2 A published report describes this variant as de novo in a patient with cardiofaciocutaneous syndrome, but the retrieved evidence does not document the parental confirmation details needed to assign PS2 points. Details ▾Hide ▴
Rule
Point-based de novo scoring; Strong at 2 points, Moderate at 1 point.
Evidence considered
  • Published de novo case title for p.Val600Gly
  • RASopathy PS2 uses point-based scoring
Still missing
  • Maternity and paternity confirmation were not available in the retrieved evidence.
  • Phenotype-specific point assignment under the RASopathy framework was not documented in the retrieved evidence.
Sources
cspec ↗PMID:20735442 ↗clinvar ↗
PS4 This variant has been observed in at least one published germline case and in somatic cancer databases, but the retrieved evidence does not provide the RASopathy point total or a case-control enrichment analysis needed to assign PS4. Details ▾Hide ▴
Rule
Point-based prevalence evidence; Supporting at 1 point, Moderate at 3 points, Strong at 5 points.
Evidence considered
  • One published germline case report
  • ClinVar expert-panel classification
  • COSMIC somatic observations
Still missing
  • No germline case-count or point total sufficient for PS4 was documented in the retrieved evidence.
  • Somatic recurrence does not by itself establish germline enrichment for RASopathy.
Sources
cspec ↗PMID:20735442 ↗clinvar ↗
PM6 A published de novo case was identified, but the retrieved evidence does not provide enough detail to determine whether the report should be scored as assumed de novo under the RASopathy PM6 point system. Details ▾Hide ▴
Rule
Point-based assumed de novo scoring; Supporting at 0.5 point, Moderate at 1 point, Strong at 2 points.
Evidence considered
  • Published de novo case title for p.Val600Gly
  • RASopathy PM6 point-based framework
Still missing
  • Parental study details were not available in the retrieved evidence.
  • The appropriate PM6 point assignment could not be confirmed from the retrieved evidence.
Sources
cspec ↗PMID:20735442 ↗
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
Supporting at at least 3 informative meioses, Moderate at at least 5, Strong at at least 7.
Evidence considered
  • No informative meioses identified
Still missing
  • No family segregation data were available in the retrieved evidence.
Sources
cspec ↗
PP2 This is a missense variant in a gene where missense disease is relevant, but the retrieved evidence did not provide the BRAF missense z score needed to determine whether the >3.09 threshold is met. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
  • PP2 threshold in CSPEC requires missense z score >3.09
Still missing
  • The gene-level missense z score was not present in the retrieved evidence.
Sources
cspec ↗
BS2 No observations in unaffected individuals were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
Point-based evidence from healthy individuals.
Evidence considered
  • No unaffected-carrier data identified
Still missing
  • No healthy carrier evidence was available in the retrieved evidence.
Sources
cspec ↗
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Requires one informative meiosis showing lack of segregation.
Evidence considered
  • No family non-segregation evidence identified
Still missing
  • No informative non-segregation evidence was available in the retrieved evidence.
Sources
cspec ↗
BP2 No phase data or alternate molecular explanation in the same gene were identified, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
Point-based evidence for an alternative molecular cause in the same gene.
Evidence considered
  • No phase or alternate-cause evidence identified
Still missing
  • No in trans or cis data with another relevant variant were available.
Sources
cspec ↗
BP5 No alternate molecular diagnosis or phenotype inconsistency evidence was identified, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
Point-based evidence for an alternative molecular cause in a different gene or a phenotype fully explained by another cause.
Evidence considered
  • No alternate-cause evidence identified
Still missing
  • No alternative molecular explanation was available in the retrieved evidence.
Sources
cspec ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, and the BRAF RASopathy specification lists PVS1 as not applicable for this framework. Details ▾Hide ▴
VCEP rule
Not applicable under the BRAF RASopathy VCEP framework.
Evidence considered
  • RASopathy BRAF CSPEC marks PVS1 not applicable
  • Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PS1 N/APS1 is intended for a different nucleotide change that produces the same amino acid substitution. The available expert-panel record is for this same c.1799T>G change rather than a separate same-protein comparator. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
  • PS1 rule requires a different nucleotide change with the same amino acid consequence
  • ClinVar expert-panel record is for c.1799T>G itself
Sources
cspec ↗clinvar ↗
PM3 VCEPPM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
  • CSPEC marks PM3 not applicable
Sources
cspec ↗
PM4 N/AThis variant is a missense substitution and does not produce an in-frame protein length change or stop-loss effect. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
  • Missense substitution p.Val600Gly
Sources
cspec ↗
PP4 VCEPPP4 is not applicable in this BRAF RASopathy framework because phenotype-based case evidence is incorporated into PS4. Details ▾Hide ▴
VCEP rule
Not applicable; see PS4.
Evidence considered
  • CSPEC marks PP4 not applicable
Sources
cspec ↗
BS3 VCEPBS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
  • CSPEC marks BS3 not applicable
Sources
cspec ↗
BP1 N/AIn this RASopathy framework, BP1 is reserved for truncating or loss-of-function variants in genes where gain-of-function missense variants are the established disease mechanism. This variant is missense, so BP1 does not apply. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
  • Variant is missense
  • not truncating or loss-of-function
Sources
cspec ↗
BP3 VCEPBP3 is not applicable in this RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
  • CSPEC marks BP3 not applicable
Sources
cspec ↗
BP6 VCEPBP6 is not used in this VCEP framework. Details ▾Hide ▴
VCEP rule
Not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • CSPEC marks BP6 not applicable
Sources
cspec ↗
BP7 N/AThis is not a synonymous or intronic noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible noncoding variant with no predicted splice impact.
Evidence considered
  • Missense variant p.Val600Gly
  • SpliceAI reviewed but BP7 is restricted to synonymous or certain noncoding variants
Sources
cspec ↗spliceai ↗

Identifiers

Gene
BRAF
Transcript
NM_001354609.1
Coding (HGVS c.)
NM_001354609.1:c.1799T>G
Protein (HGVS p.)
NP_001341538.1:p.(Val600Gly)
GRCh38
chr7:140753336 A>C
GRCh37
chr7:140453136 A>C
ClinVar
40389, 13968
COSMIC
COSV56080151

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…
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.

SpliceAI and Pangolin

SpliceAI acceptor lossat +57 bp
0.070
SpliceAI acceptor gainat +0 bp
0.000
SpliceAI donor lossat -61 bp
0.110
SpliceAI donor gainat +22 bp
0.000
Pangolin splice lossmagnitude shown
-0.290
Pangolin splice gain
0.070

Other predictors

REVEL
0.925
BayesDel
0.357

How the predictions were used

PP3 SupportingComputational evidence supports a damaging missense effect. REVEL is 0.925, which is above the RASopathy PP3 threshold of 0.7; BayesDel is 0.357299; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, which is consistent with this being primarily a missense effect rather than a splice-altering variant. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7.
Evidence considered
  • REVEL 0.925
  • BayesDel 0.357299
  • SpliceAI max delta 0.11
Sources
cspec ↗revelbayesdelspliceai ↗
BP4 Available computational evidence does not support BP4. REVEL is 0.925, which is above the benign BP4 threshold of 0.3, and BayesDel is 0.357299; although SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, the missense predictor result does not support a benign interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
  • REVEL 0.925
  • BayesDel 0.357299
  • SpliceAI max delta 0.11
Sources
cspec ↗revelbayesdelspliceai ↗
BP7 N/AThis is not a synonymous or intronic noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible noncoding variant with no predicted splice impact.
Evidence considered
  • Missense variant p.Val600Gly
  • SpliceAI reviewed but BP7 is restricted to synonymous or certain noncoding variants
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.925. BayesDel score = 0.357299.

8 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

  • Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.
    Champion KJ et al. · 2011
    No paper-specific finding is recorded.
    PMID 20735442 ↗
  • Mutations of the BRAF gene in human cancer.
    No paper-specific finding is recorded.
    PMID 12068308 ↗
  • Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
    No paper-specific finding is recorded.
    PMID 15035987 ↗
  • BRAF mutation predicts sensitivity to MEK inhibition.
    No paper-specific finding is recorded.
    PMID 16273091 ↗
  • Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
    No paper-specific finding is recorded.
    PMID 26287849 ↗
  • Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
    No paper-specific finding is recorded.
    PMID 28783719 ↗
  • Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.
    Shirley BC et al. · 2018
    No paper-specific finding is recorded.
    PMID 31275557 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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 Recorded maximum delta 0.110 Open source ↗
ClinVar 1 Uncertain significance · 1 Pathogenic 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

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 Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40389)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.925. BayesDel score = 0.357299.

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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56080151, n = 27 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.