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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.722C>A
p.Thr241Lys  ·  BRAF
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Classification rationale
1

The BRAF c.722C>A (p.Thr241Lys) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in reference populations.

gnomad_v2 ↗ gnomad_v4 ↗
3

A different missense change at the same residue, p.Thr241Pro, is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, supporting same-residue evidence under the BRAF specification.

cspec ↗
4

Computational evidence supports a deleterious missense effect because REVEL is 0.946, above the BRAF PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.

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 (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 44829)
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 no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.946. BayesDel score = 0.468035.
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.
ResidueT241
Hotspots ↗