Classification rationale

PS3PM1PM2PP5 VUS

BRAF c.1796C>G

The BRAF c.1796C>G (p.Thr599Arg) variant has been reported in ClinVar as pathogenic, including an expert panel pathogenic classification, and is also represented in curated cancer variant resources.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.² In approved functional studies, this variant was classified as pathogenic in both MEK activation and ERK activation assays, supporting abnormal MAPK pathway signaling consistent with the disease mechanism.³ In silico evidence does not meet the BRAF RASopathy thresholds for PP3 or BP4 because REVEL is 0.359, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is 0.308415.⁴

PS3 + PM1 + PM2 + PP5 → VUS

1 clinvar ↗oncokb ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗PMID:19206169 ↗

4 revelspliceai ↗bayesdelcspec ↗

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 · 4 applied · 15 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 · 4

Strength Supporting Moderate Strong Very strong

PS3 moderate Pathogenic

In approved functional studies, this variant was listed as pathogenic in both MEK activation and ERK activation assays, consistent with abnormal downstream MAPK pathway activation. Under the BRAF RASopathy specification, results from 2 different approved assays meet PS3 at Moderate strength.

Approved MEK activation assay lists T599R as PApproved ERK activation assay lists T599R as P

cspec ↗PMID:19206169 ↗

PM1 moderate Pathogenic

Thr599 lies within the BRAF CR3 activation segment (amino acids 594-627), which the BRAF RASopathy specification defines as a critical and well-established functional region for PM1.

BRAF-specific PM1 region includes the CR3 activation segment aa 594-627Variant protein consequence is p.Thr599Arg

cspec ↗

PM2 supporting Pathogenic

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

gnomAD v2.1 absentgnomAD v4.1 absent

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP5 supporting Pathogenic

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

BRAF RASopathy specification marks PP5 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS1 No directly reviewed evidence established that this same amino acid change has already been classified as pathogenic from an independent nucleotide change or from an approved analogous RAF position analysis.

PS2 No confirmed de novo occurrence with the point threshold required by the BRAF RASopathy specification was directly established from the reviewed evidence.

PS4 Affected-case enrichment meeting the RASopathy point threshold was not directly established from the reviewed evidence, so PS4 was not applied.

PM5 No directly reviewed codon-level evidence established a different pathogenic missense change at this same codon at the strength required by the BRAF RASopathy specification.

PM6 No assumed or confirmed de novo point total for this variant was directly established from the reviewed evidence, so PM6 was not applied.

PP1 No segregation data were identified showing this variant cosegregates with disease across the number of informative meioses required for PP1.

PP2 The BRAF RASopathy specification uses a missense constraint threshold of z score greater than 3.09 for PP2, and that gene-level value was not directly available in the reviewed evidence.

PP3 Computational evidence does not meet the BRAF RASopathy threshold for PP3.

Benign

BA1 This variant does not meet BA1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.05%.

BS1 This variant does not meet BS1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.025%.

BS2 No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2.

BS4 No nonsegregation data were identified for this variant, so BS4 was not applied.

BP2 No phase or co-occurrence evidence meeting the RASopathy point-based BP2 thresholds was identified.

BP4 Computational evidence does not meet the BRAF RASopathy threshold for BP4.

BP5 No alternative molecular explanation data meeting the RASopathy point-based BP5 thresholds were identified.

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 (4 clinical laboratories) 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 = 0.00). REVEL score = 0.359. BayesDel score = 0.308415.

SpliceAI ↗

Functional Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56167356, n = 2 times).

Hotspots

This variant does not lie 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.

Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes:

PMID 19206169 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 moderate

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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