Variant classification summary

NM_004333.6:c.1799T>A

BRAF · NP_004324.2:p.(Val600Glu) · NM_004333.6

GRCh37: chr7:140453136 A>T · GRCh38: chr7:140753336 A>T

Gene: BRAF Transcript: NM_004333.6

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM1 moderate PP3 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Val600Glu)

gnomAD AF

1.2399855665680052e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS1 strong: historical BRAF V599E is the equivalent established activating p.Val600Glu change.

2

PM1 moderate: Val600 lies within the VCEP-approved CR3 activation segment.

3

PS3 supporting: BRAF V600E shows abnormal MEK/ERK pathway activation in cell-based studies.

4

PP3 supporting: REVEL 0.931 exceeds the BRAF VCEP threshold of 0.7.

Final determination: BRAF VCEP Rule11 is satisfied by one strong pathogenic criterion (PS1) and one moderate pathogenic criterion (PM1), resulting in a Likely Pathogenic classification.

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: BRAF c.1799T>A is a missense p.Val600Glu substitution, not a loss-of-function variant eligible for PVS1.	cspec
PS1	Met	Met, strong: historical BRAF V599E is the equivalent established activating p.Val600Glu alteration under current transcript numbering.	cspec PMID:12068308 PMID:15035987
PS2	Not assessed	Not assessed: no proband-level de novo observation or parental maternity-and-paternity testing is documented for this variant.	cspec
PS3	Met	Met at Supporting: BRAF V600E shows abnormal ERK/MEK pathway activation in two biologically relevant cell-based studies, but validation controls do not justify Moderate strength.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:20179705 PMID:19251651
PS4	Not assessed	Not assessed: no validated RASopathy phenotype, case-control enrichment, or VCEP PS4 point count is available for BRAF p.Val600Glu.	cspec PMID:12447372 PMID:12619120
PM1	Met	Met, moderate: residue 600 lies within the VCEP-approved CR3 activation segment domain spanning amino acids 594-627.	cspec
PM2	Not met	Not met: the variant is observed in gnomAD v2.1 non-cancer exomes at 1/236,728 alleles, whereas the BRAF VCEP requires complete absence.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF RASopathy VCEP specifies autosomal dominant inheritance and designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.Val600Glu is a missense substitution with no protein-length change, so the BRAF PM4 rule does not apply.	cspec
PM5	Not assessed	Not assessed: no qualifying same-residue comparator was collected, but the comparator search ended with an HTTP 429 retrieval failure.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no apparently de novo occurrence or parental testing is documented to support the BRAF VCEP PM6 point thresholds.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected-family segregation observations are documented for this variant.	cspec
PP2	Not assessed	Not assessed: the required BRAF missense z score >3.09 is not available, despite target allele-frequency data.	cspec gnomad_v2 gnomad_v4
PP3	Met	Met at supporting strength: REVEL 0.931 exceeds the BRAF VCEP PP3 threshold of >=0.7 for missense variants.	cspec revel
PP4	N/A	Not applicable: the governing BRAF VCEP explicitly designates PP4 as not applicable and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the BRAF VCEP excludes PP5, and ClinVar shows zero expert-panel submissions for this exact variant.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 non-cancer exome frequency is 0.00042%, below the BRAF VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD v2.1 non-cancer exome frequency is 0.00042%, below the BRAF VCEP BS1 threshold of 0.025%.	cspec gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes, but no qualifying healthy carrier or phenotype data are available for the BRAF VCEP BS2 point score.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the governing BRAF RASopathy VCEP specification explicitly designates BS3 as Not Applicable.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected relative or informative meiosis demonstrates that this variant fails to segregate with disease.	cspec
BP1	N/A	Not applicable: p.Val600Glu is missense, whereas the BRAF VCEP BP1 rule is restricted to specified truncating loss-of-function variants.	cspec
BP2	Not assessed	Not assessed: no documented second pathogenic variant, alternative molecular cause, or cis/trans phase is available for BRAF p.Val600Glu.	cspec
BP3	N/A	Not applicable: BRAF c.1799T>A is a missense p.Val600Glu substitution, not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: REVEL 0.931 is above the BRAF VCEP BP4 threshold of <=0.3 for missense variants.	cspec revel
BP5	Not assessed	Not assessed: no individual-level alternate pathogenic cause, qualifying phenotype, or VCEP BP5 point calculation is documented.	cspec clinvar
BP6	N/A	Not applicable: the BRAF VCEP excludes BP6, and no exact-variant ClinVar benign expert-panel assertion exists.	cspec clinvar
BP7	N/A	Not applicable: the variant changes Val600 to Glu and is not synonymous, whereas BP7 is restricted to synonymous variants.	cspec

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