The BRAF c.1595G>A (p.Cys532Tyr, p.C532Y) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at supporting strength under the RASopathy VCEP framework.2 Approved RASopathy VCEP functional assay frameworks are available, but no variant-specific approved functional study result for p.(Cys532Tyr) was identified, so PS3 was not applied.3 Computational evidence supports a deleterious effect because REVEL is 0.912, above the VCEP PP3 threshold of 0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.00 and BayesDel is 0.376689; these findings support PP3 and do not support BP4.4 This missense change does not meet PM1 because the RASopathy VCEP limits PM1 in BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627), and codon 532 is outside the specified amino acid regions.5
BRAF
Final classification
VUS
BRAF c.1595G>A · p.Cys532Tyr
BRAF
The BRAF c.1595G>A (p.Cys532Tyr, p.C532Y) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Likely pathogenic, including expert panel review by 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 was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3PP5
VUS
BRAF c.1595G>A
PM2 + PP3 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
cspec ↗revelspliceai ↗bayesdel
5
cspec ↗
Gene diagram
· NM_001354609.1 · variants mapped to exon structure
BRAF
NM_001354609.1
Fetching transcript structure from UCSC…
Applied criteria · 3 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
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 Likely pathogenic (4 clinical laboratories) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.912. BayesDel score = 0.376689.
Functional
Unknown Oncogenic Effect
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