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.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in reference populations.2 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.3 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 0.04.4
BRAF
Final classification
Likely Pathogenic
BRAF c.722C>A · p.Thr241Lys
BRAF
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PM1PM2PM5PP3PP5
Likely Pathogenic
BRAF c.722C>A
PM1 + PM2 + PM5 + PP3 + PP5
→
Likely Pathogenic
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
revelspliceai ↗cspec ↗
Gene diagram
· NM_001354609.1 · variants mapped to exon structure
BRAF
NM_001354609.1
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.946. BayesDel score = 0.468035.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links