Classification rationale

PM1PM2PP2PP3PP5 VUS

BRAF c.793G>C

The BRAF c.793G>C (p.Gly265Arg) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert panel likely pathogenic classification and additional pathogenic or likely pathogenic clinical laboratory submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.² Computational evidence supports a damaging missense effect, with REVEL 0.917 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.403109 in a deleterious direction, and SpliceAI showing no significant predicted splice impact (maximum delta score 0.00).³

PM1 + PM2 + PP2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗revelbayesdelspliceai ↗

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

PM1 moderate Pathogenic

This missense variant affects p.(Gly265Arg) in BRAF exon 6. The BRAF RASopathy specification explicitly recognizes exon 6 as a PM1 region, so PM1 is met at moderate strength even though this variant was not identified as a statistically significant cancer hotspot.

Variant localizes to exon 6BRAF RASopathy specification lists exon 6 as a PM1 regionCancer Hotspots did not show a significant hotspot

cspec ↗hotspots ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold requiring absence from controls.

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

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP2 supporting Pathogenic

This is a missense variant in BRAF, and the observed missense constraint z score is 3.99, which is above the BRAF RASopathy PP2 threshold of 3.09. This supports PP2 at supporting strength.

BRAF missense z score 3.99Threshold for PP2 is >3.09

cspec ↗

PP3 supporting Pathogenic

Computational evidence supports a damaging missense effect. REVEL is 0.917, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.403109 in a deleterious direction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting interpretation as a missense rather than splicing effect.

REVEL 0.917BayesDel 0.403109SpliceAI max delta 0.00

cspec ↗spliceai ↗

PP5 supporting Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.

BRAF RASopathy specification marks PP5 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PS1 No alternate nucleotide change producing the same amino acid substitution was identified, so available evidence does not support PS1 for this variant.

PS2 No confirmed de novo occurrence with sufficient case-level phenotypic detail and parental confirmation was identified, so PS2 cannot be applied from the available evidence.

PS3 Approved BRAF functional assay frameworks are available, but no variant-specific result for p.(Gly265Arg) was identified in the retrieved materials.

PS4 This variant is reported in ClinVar and has been observed once in COSMIC, but no case-count or case-control evidence meeting the RASopathy point-based PS4 framework was identified.

PM5 No different pathogenic or likely pathogenic missense change at codon 265 was identified from the available evidence, so PM5 is not met.

PM6 No probable de novo observation with enough evidence for point assignment was identified, so PM6 cannot be applied from the available evidence.

PP1 No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the BA1 threshold of 0.05%.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the BS1 threshold of 0.025%.

BS2 No data were identified showing this variant in unaffected individuals at a level meeting the RASopathy BS2 point framework, so BS2 cannot be applied.

BS4 No lack-of-segregation evidence in an informative family was identified, so BS4 cannot be applied.

BP2 No evidence was identified for an alternative molecular explanation in cis or trans meeting the RASopathy BP2 point framework, so BP2 cannot be applied.

BP4 Available computational evidence does not support BP4.

BP5 No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistency meeting the RASopathy BP5 point framework, so BP5 cannot be applied.

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 Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely 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 = 0.917. BayesDel score = 0.403109.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

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; COSV109420825, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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