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
Final classification
VUS
PM2PP3PP5
BRAF
c.1595G>A
p.Cys532Tyr
This variant
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 ↗
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 · 3 applied · 16 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy VCEP requirement that PM2 be applied at supporting strength when the variant is absent from population controls.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP3
supporting
Pathogenic
For this missense variant, the REVEL score is 0.912, which is above the RASopathy VCEP PP3 threshold of 0.7 and supports a deleterious protein effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice mechanism, and the BayesDel score is 0.376689, which is directionally supportive of a damaging effect.
REVEL 0.912SpliceAI max delta score 0.00BayesDel 0.376689
Assessed · not applied
· 4 not met · 12 not assessed
Pathogenic
PS1
No verified evidence was identified showing a different nucleotide change causing the same amino acid substitution as an established pathogenic variant in BRAF or the analogous RAF1 residue, so PS1 was not assessed.
PS2
No case-level evidence was identified confirming this variant occurred de novo with confirmed maternity and paternity in an affected individual, so PS2 was not assessed.
PS3
RASopathy VCEP-approved functional assay frameworks are available, but no variant-specific approved assay result for p.(Cys532Tyr) was identified in the reviewed materials, so PS3 was not applied.
PS4
This variant is reported in ClinVar, but no verified count of unrelated affected individuals or point-based case enrichment data was identified for this variant, so PS4 was not assessed.
PM1
The RASopathy VCEP restricts PM1 for BRAF to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627).
PM5
No verified same-codon pathogenic missense comparator was identified for this residue in the reviewed materials, so PM5 was not assessed.
PM6
No case-level evidence was identified showing this variant was assumed de novo without full parental confirmation, so PM6 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
PP2
This is a missense variant in BRAF, but no gnomAD missense z score was provided in the reviewed materials to verify that the VCEP threshold of greater than 3.09 is met, so PP2 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 stand-alone threshold of 0.05%, so BA1 is not met.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 threshold of 0.025%, so BS1 is not met.
BS2
No evidence was identified showing this variant in unaffected adult individuals under the VCEP point-based BS2 framework, so BS2 was not assessed.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP2
No evidence was identified that this variant occurred with an alternative molecular explanation in the same gene, so BP2 was not assessed.
BP4
For this missense variant, the REVEL score is 0.912, which is above the benign BP4 threshold of 0.3, so BP4 is not met.
BP5
No evidence was identified for an alternative molecular explanation in a different gene or for a phenotype fully explained by another variant, so BP5 was not assessed.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
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