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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.1799T>G
p.Val600Gly  ·  BRAF
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Classification rationale
1

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.

clinvar ↗
2

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

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:20735442 ↗ cspec ↗
4

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.

cspec ↗ spliceai ↗
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 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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.925. BayesDel score = 0.357299.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56080151, n = 27 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueV600
Hotspots ↗