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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.739T>G
p.Phe247Val  ·  BRAF
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Classification rationale
1

The BRAF c.739T>G (p.Phe247Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is likely pathogenic with expert panel review.

clinvar ↗
2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports PM2 at supporting strength under the BRAF RASopathy specification.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗ cspec ↗
3

This missense variant lies in BRAF exon 6, a region explicitly designated by the RASopathy VCEP for PM1 application, and other pathogenic or likely pathogenic missense changes have been reported at the same codon 247, supporting PM5 at moderate strength.

cspec ↗ clinvar ↗
4

Computational evidence supports a deleterious missense effect because REVEL is 0.921, above the VCEP PP3 threshold of 0.7, BayesDel is positive at 0.434669, and SpliceAI shows only a possible splice signal with a max delta score of 0.20.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 44830)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
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 ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.921. BayesDel score = 0.434669.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueF247
Hotspots ↗