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
Final classification
Likely Pathogenic
PM1PM2PM5PP3PP5
BRAF
c.722C>A
p.Thr241Lys
This variant
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 ↗
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
review
Pathogenic
This missense variant is located in BRAF exon 6, which is explicitly listed by the BRAF RASopathy specification as a critical and well-established functional region for PM1.
Variant maps to exon 6BRAF VCEP lists exon 6 as PM1-eligible
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy specification requirement that the variant be absent from controls for PM2_Supporting.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PM5
moderate
review
Pathogenic
A different missense change at the same residue, p.(Thr241Pro), is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, satisfying the BRAF same-codon PM5 rule for one established pathogenic or likely pathogenic residue change.
Same-residue comparator p.(Thr241Pro) labeled P/LP in approved VCEP materials
PP3
supporting
review
Pathogenic
Computational evidence supports a deleterious missense effect: REVEL is 0.946, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.468035, and SpliceAI predicts no meaningful splice disruption (max delta score 0.04), supporting a protein-level rather than splice-mediated effect.
REVEL 0.946BayesDel 0.468035SpliceAI max delta 0.04
Assessed · not applied
· 4 not met · 10 not assessed
Pathogenic
PS1
No evidence was identified that a different nucleotide change produces the same p.(Thr241Lys) amino acid substitution with an established pathogenic classification.
PS2
No parentage-confirmed de novo report for this exact variant was identified from the available evidence, so the point-based de novo criterion cannot be assigned here.
PS3
Published and curated functional materials were available for review, but no approved functional assay result for p.(Thr241Lys) itself was identified here, so PS3 cannot be assigned on the current evidence.
PS4
This variant has been reported in ClinVar, including by the ClinGen RASopathy expert panel, but the available evidence does not provide the case counts or PS4 point total needed for the RASopathy point-based enrichment criterion.
PM6
No assumed de novo report with sufficient case-level detail for this exact variant was identified, so PM6 cannot be assigned from the current evidence.
PP1
No segregation data were identified for this exact variant, so co-segregation evidence cannot be counted.
PP2
The BRAF RASopathy specification allows PP2 when the gnomAD missense z score is greater than 3.09, but a citable gene-level constraint value was not provided in the case materials, so this criterion is left for manual confirmation.
Benign
BA1
This variant is absent from gnomAD and does not meet the BRAF RASopathy BA1 stand-alone benign frequency threshold of 0.05%.
BS1
This variant is absent from gnomAD and does not meet the BRAF RASopathy BS1 benign frequency threshold of 0.025%.
BS2
No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be applied.
BP2
No phase or alternate-molecular-explanation data were identified to support BP2.
BP4
Computational results do not support a benign interpretation for this missense change because REVEL is 0.946, which is above the benign BP4 threshold of 0.3.
BP5
No evidence was identified for an alternate molecular explanation meeting the point threshold for BP5.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
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