LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-01
Case ID: NM_004333.6_c.1781A_G_20261101_052331
Framework: ACMG/AMP 2015
Variant classification summary

NM_004333.6:c.1781A>G

BRAF  · NP_004324.2:p.(Asp594Gly)  · NM_004333.6
GRCh37: chr7:140453154 T>C  ·  GRCh38: chr7:140753354 T>C
Gene: BRAF Transcript: NM_004333.6
Final call
VUS
PS3 supporting PM1 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRAF
Transcript
NM_004333.6
Protein
NP_004324.2:p.(Asp594Gly)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 Supporting: variant-specific studies show impaired or absent BRAF kinase activity and abnormal signaling.
2
PM1 Moderate: p.Asp594Gly lies within the VCEP-defined CR3 activation segment at amino acids 594-627.
3
PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.
4
PP3 Supporting: REVEL 0.989 exceeds the VCEP missense threshold of 0.7.
Final determination: Under the BRAF VCEP Version 2.3 framework, no pathogenic or benign combination rule is met by one moderate and three supporting criteria, so the variant is classified as VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: the BRAF VCEP explicitly marks PVS1 not applicable, and c.1781A>G produces the missense change p.(Asp594Gly).
cspec pvs1_variant_assessment
PS1 Not assessed Not assessed: D594G is reported, but no eligible previously established pathogenic comparator is documented in the reviewed VCEP-governed evidence.
cspec PMID:14612909 PMID:14688025 PMID:26498038 PMID:28783719 PMID:23352452
PS2 Not assessed Not assessed: no documented germline proband result, confirmed maternity and paternity, parental testing, or disease phenotype is available for the de novo requirement.
cspec PMID:14612909 PMID:14688025
PS3 Met Met, Supporting: two variant-specific studies show impaired or absent BRAF kinase activity with abnormal RAS-dependent ERK signaling, but the VCEP table does not list this variant.
cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:28783719 PMID:23352452
PS4 Not assessed Not assessed: available reports are somatic cancer observations without RASopathy phenotype points or case-control counts needed to evaluate the VCEP's ≥1-point PS4 rule.
cspec PMID:14612909 PMID:14688025 PMID:23352452 PMID:26498038
PM1 Met Met, moderate: residue 594 is the lower boundary of the VCEP-approved CR3 activation segment spanning amino acids 594-627.
cspec vcep_raf_alignment PMID:26498038
PM2 Met Met at Supporting: the variant is absent from both available all-comers gnomAD v2.1 and v4.1 control records.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the BRAF VCEP explicitly designates PM3 as not applicable for this autosomal-dominant RASopathy framework.
cspec
PM4 N/A Not applicable: p.(Asp594Gly) is a missense substitution with no insertion, deletion, stop-loss event, or protein-length change.
cspec pvs1_variant_assessment
PM5 Not assessed Not assessed: alternate codon-594 substitutions are reported, but their VCEP likely-pathogenic status and required proband evidence are unavailable.
cspec pm5_candidates PMID:20141835 PMID:26498038
PM6 Not assessed Not assessed: no germline proband observation or parent-negative testing is documented to support an assumed de novo event.
cspec PMID:14612909 PMID:14688025
PP1 Not assessed Not assessed: zero informative meioses or affected-relative genotype and phenotype data are documented for the required co-segregation evaluation.
cspec PMID:14612909 PMID:14688025
PP2 Not assessed Not assessed: the required BRAF missense z score is unavailable, so comparison with the VCEP threshold of >3.09 cannot be made.
cspec gnomad_v2 gnomad_v4
PP3 Met Met: REVEL 0.989 meets the VCEP PP3 threshold of ≥0.7 for missense variants.
cspec revel
PP4 N/A Not applicable: the BRAF VCEP explicitly excludes PP4 and directs phenotype evidence to PS4.
cspec
PP5 N/A Not applicable: the BRAF VCEP states PP5 is not for use in this VCEP.
cspec
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the VCEP's ≥0.05% filtering allele frequency threshold.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the VCEP's ≥0.025% filtering allele frequency threshold.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: no qualifying healthy individual or genotype-and-phenotype evidence is available to assign the VCEP's BS2 points.
cspec
BS3 N/A Not applicable: the BRAF VCEP v2.3 explicitly marks BS3 as not applicable for this framework.
cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4 Not assessed Not assessed: no informative meiosis or affected-family-member genotype and phenotype comparison is documented for non-segregation.
cspec PMID:14612909 PMID:14688025
BP1 N/A Not applicable: p.Asp594Gly is missense, whereas the VCEP BP1 rule is restricted to specified truncating variant types.
cspec
BP2 Not assessed Not assessed: a tumor report shows BRAF D594G with KRAS A59E, but neither germline cis/trans phase nor a RASopathy phenotype is documented to establish the ≥ (-1) Point BP2 threshold.
cspec PMID:26498038
BP3 N/A Not applicable: the BRAF VCEP explicitly marks BP3 not applicable, and c.1781A>G is a missense substitution.
cspec pvs1_variant_assessment
BP4 Not met Not met: REVEL 0.989 exceeds the VCEP BP4 threshold of ≤0.3 for missense variants.
cspec revel
BP5 Not assessed Not assessed: one somatic KRAS co-occurrence does not establish the VCEP's required alternative RASopathy cause or BP5 point value.
cspec PMID:26498038
BP6 N/A Not applicable: the BRAF VCEP states BP6 is not for use in this VCEP.
cspec
BP7 N/A Not applicable: the variant is exonic missense, whereas BP7 covers synonymous, qualifying intronic, or non-coding variants.
cspec
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