Classification rationale

PS3PM1PM2PP3PP5 VUS

BRAF c.1787G>T

The BRAF c.1787G>T (p.Gly596Val) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic with expert-panel review.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.² In a published functional study, BRAF p.Gly596Val caused abnormal zebrafish developmental phenotypes and showed downstream ERK activation, consistent with dysregulated MAPK signaling.³ Computational evidence supports a deleterious missense effect, with REVEL 0.989 above the BRAF PP3 threshold of 0.7, BayesDel 0.588239, and SpliceAI predicting no significant splice effect with a maximal delta score of 0.07.⁴

PS3 + PM1 + PM2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:19376813 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

4 revelbayesdelspliceai ↗cspec ↗

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.

Gene diagram · NM_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 5 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 5

Strength Supporting Moderate Strong Very strong

PS3 supporting review Pathogenic

In a published functional study, expression of BRAF p.(Gly596Val) in zebrafish caused abnormal embryonic elongation and developmental abnormalities, and phospho-ERK assays showed downstream ERK activation, consistent with dysregulated MAPK signaling. These data support an abnormal functional effect consistent with the disease mechanism and support PS3 at Supporting strength.

Zebrafish developmental assay for BRAF G596VPhospho-ERK functional readoutRASopathy VCEP approved functional studies resource

PMID:19376813 ↗cspec ↗

PM1 moderate review Pathogenic

This missense variant affects Gly596, which lies within the BRAF CR3 activation segment (amino acids 594-627), a critical and well-established functional domain specifically listed for PM1 in the BRAF RASopathy specification. This meets PM1 at Moderate strength.

Variant protein consequence p.(Gly596Val)BRAF CR3 activation segment 594-627 listed in CSPEC

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the BRAF RASopathy specification, absence from gnomAD meets PM2 at Supporting strength.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 supporting review Pathogenic

Computational evidence supports a deleterious missense effect. REVEL is 0.989, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.588239, and SpliceAI predicts no significant splice impact with a maximal delta score of 0.07. For this missense variant, the available computational evidence supports PP3 at Supporting strength.

REVEL 0.989BayesDel 0.588239SpliceAI max delta 0.07

spliceai ↗cspec ↗

PP5 supporting review Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

BRAF CSPEC marks PP5 not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS1 No different nucleotide change producing the same amino acid substitution, p.(Gly596Val), was identified from the reviewed evidence, so PS1 is not met.

PS2 Published disease association is strong, but no directly reviewed case-level evidence in the available materials confirmed a de novo occurrence with sufficient parentage documentation to score PS2 points.

PS4 This variant has been reported in ClinVar and has been observed in somatic cancer databases, but the available materials do not provide the unrelated germline proband counts or point-based case evidence needed to apply the BRAF RASopathy PS4 rule.

PM5 A different missense change at the same codon, p.(Gly596Cys), was identified in ClinVar, but it has conflicting classifications of pathogenicity rather than an established pathogenic or likely pathogenic classification.

PM6 No directly reviewed case-level evidence showed this variant as assumed de novo with the documentation needed to assign PM6 points.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

PP2 The BRAF RASopathy specification allows PP2 when the missense constraint z score is greater than 3.09, but no directly reviewed gene-level missense z score was identified in the available materials for this adjudication.

Benign

BA1 This variant is absent from gnomAD and does not reach the BRAF RASopathy BA1 threshold of at least 0.05% filtering allele frequency.

BS1 This variant is absent from gnomAD and does not reach the BRAF RASopathy BS1 threshold of at least 0.025% filtering allele frequency.

BS2 No evidence was identified showing this variant in unaffected individuals in a quantity sufficient to assign BS2 points.

BS4 No non-segregation evidence was identified for this variant, so BS4 cannot be applied.

BP2 No phase data or point-based evidence were identified to support BP2.

BP4 Available computational evidence does not support a benign effect.

BP5 No evidence was identified for an alternate molecular explanation with point-based support to apply BP5.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.989. BayesDel score = 0.588239.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99951808, n = 1 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles ha

PMID 19376813 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supporting

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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