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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.1595G>A
p.Cys532Tyr  ·  BRAF
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Classification rationale
1

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.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at supporting strength under the RASopathy VCEP framework.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗
4

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.

cspec ↗ spliceai ↗
5

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.

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 Likely pathogenic (4 clinical laboratories) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.912. BayesDel score = 0.376689.
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.
ResidueC532
Hotspots ↗