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

PS3 moderate PM1 moderate PM2 supporting 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

PS3 (Moderate): two or more VCEP-approved functional assays show V600E increases MEK/ERK pathway signaling.

2

PM1 (Moderate): residue 600 lies in the VCEP-approved CR3 activation segment (amino acids 594-627).

3

PM2 (Supporting): the variant is effectively absent from gnomAD, with 2 of 1,612,922 v4.1 exome alleles (AF 1.24e-06).

4

PP3 (Supporting): REVEL 0.931 exceeds the VCEP missense cutoff of 0.7.

5

Overall: Likely Pathogenic, reached from 2 moderate plus 2 supporting criteria under the BRAF v2.3 combination rules.

Final determination: Under the ClinGen RASopathy Expert Panel BRAF v2.3 criteria-combination framework, 2 Pathogenic.Moderate criteria (PS3 moderate + PM1) together with >=2 Pathogenic.Supporting criteria (PM2 supporting + PP3 supporting) satisfy the Likely Pathogenic rule for '2 moderate + 2 supporting' (Rule14), with PS3_Moderate restored to the Pathogenic.Moderate partition because that code is omitted from the v2.3 payload even though the same specification declares PS3 Moderate applicable.

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 v2.3 specification marks PVS1 not applicable, and p.(Val600Glu) is a missense substitution rather than a loss-of-function change.	cspec
PS1	N/A	Not applicable: c.1799T>A is itself the canonical pathogenic p.(Val600Glu) record, so no different nucleotide change exists to serve as its comparator. Flagged for human review: the specification wording could also be read as making that identical record sufficient.	cspec clinvar pm5_candidates vcep_raf_alignment
PS2	Not assessed	Not assessed: no proband, family history, or parental testing was available to establish the confirmed de novo occurrence PS2 requires.	cspec clinvar PMID:12068308 PMID:25741868
PS3	Met	Met at moderate strength: two or more VCEP-approved functional assays show V600E increases MEK/ERK pathway signaling.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:19251651 PMID:20179705
PS4	Not assessed	Not assessed: no germline RASopathy case counts or phenotype data were available, which PS4 requires to assign points.	cspec clinvar PMID:12068308 PMID:22142829 PMID:22855150 PMID:25741868
PM1	Met	Met at moderate strength: residue 600 lies within the VCEP-approved CR3 activation segment (amino acids 594-627).	cspec vcep_raf_alignment PMID:22855150 PMID:22142829
PM2	Met	Met at supporting strength: the variant is effectively absent from gnomAD, with 2 of 1,612,922 v4.1 exome alleles (AF 1.24e-06). Strictly read, 1-2 observed alleles do not satisfy 'absent', and supporting is the only tier this ruleset allows.	cspec gnomad_v4 gnomad_v2 gnomad_canada PMID:22855150 PMID:12068308
PM3	N/A	Not applicable: BRAF v2.3 designates PM3 not applicable because BRAF RASopathy disease is inherited autosomal dominant, not recessive.	cspec
PM4	Not met	Not met: p.(Val600Glu) is a missense substitution with no protein-length change, whereas PM4 requires an in-frame indel or stop-loss change.	cspec
PM5	Not assessed	Not assessed: no other established pathogenic amino-acid change at codon 600 was identified to serve as the required comparison.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no proband or parental genotyping was available, so neither an observed nor an assumed de novo occurrence could be scored.	cspec clinvar PMID:12068308 PMID:25741868
PP1	Not assessed	Not assessed: no family pedigree or informative meioses were available to test co-segregation of the variant with disease.	cspec clinvar PMID:25741868
PP2	Not assessed	Not assessed: no BRAF missense z score or gnomAD gene-constraint metric was available, which PP2 requires.	cspec
PP3	Met	Met at supporting strength: REVEL 0.931 exceeds the VCEP missense threshold of 0.7.	cspec revel
PP4	N/A	Not applicable: BRAF v2.3 routes phenotype-specificity evidence to PS4 and explicitly designates PP4 not applicable.	cspec
PP5	Not met	Not met: the ClinVar record has 0 expert-panel (three-star) submissions, which PP5 requires to trigger.	cspec clinvar
BA1	Not met	Not met: even the highest subpopulation frequency (3.27e-05, South Asian) falls about 15-fold below the 0.05% BA1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: even the highest subpopulation frequency (3.27e-05, South Asian) falls clearly below the 0.025% BS1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not met	Not met: no homozygotes were observed and the 1-2 heterozygous carriers carry no phenotype information, so no BS2 points are awarded.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS3	N/A	Not applicable: BRAF v2.3 explicitly marks BS3 not applicable, so no benign functional evidence criterion is assigned.	cspec
BS4	Not assessed	Not assessed: no family pedigree or affected-relative genotypes were available to demonstrate non-segregation of the variant.	cspec clinvar PMID:25741868
BP1	N/A	Not applicable: BP1 targets truncating variants, whereas p.(Val600Glu) is a missense substitution in a gene whose mechanism is gain of function.	cspec
BP2	Not assessed	Not assessed: no second BRAF pathogenic variant or phase determination was available to establish an alternative molecular cause.	cspec
BP3	N/A	Not applicable: BRAF v2.3 marks BP3 not applicable, and this is a single-residue substitution rather than an in-frame length change.	cspec
BP4	Not met	Not met: REVEL 0.931 is far above the 0.3 missense threshold BP4 requires for benign support.	cspec revel
BP5	Not assessed	Not assessed: no co-occurring causative variant or phenotype severity data were available to assign negative points.	cspec
BP6	Not met	Not met: the ClinVar record has 0 expert-panel (three-star) submissions, and none of its assertions are benign.	cspec clinvar
BP7	N/A	Not applicable: c.1799T>A is a coding missense change, not a synonymous, intronic, or non-coding variant as BP7 requires.	cspec

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