Variant classification summary

NM_004333.6:c.1790T>G

BRAF · NP_004324.2:p.(Leu597Arg) · NM_004333.6

GRCh37: chr7:140453145 A>C · GRCh38: chr7:140753345 A>C

Gene: BRAF Transcript: NM_004333.6

Final call

VUS

PS3 moderate PM1 moderate PP3 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Leu597Arg)

gnomAD AF

6.20073515916047e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Moderate: p.L597R increased phospho-MEK and phospho-ERK in two approved functional assay types.

2

PM1 Moderate: residue 597 lies within BRAF's VCEP-defined CR3 activation segment.

3

PP3 Supporting: REVEL 0.964 exceeds the BRAF VCEP threshold of 0.7.

Final determination: Under the BRAF VCEP Version 2.3 framework, two moderate criteria plus only one supporting criterion satisfy no pathogenic rule, and no benign rule is met; the result is 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 VCEP explicitly excludes PVS1, and this variant is a missense p.(Leu597Arg) substitution rather than a listed null consequence.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: exact L597R reports are available, but no previously established pathogenic comparator is documented under the VCEP rule.	cspec PMID:22798288 PMID:24933606 vcep_raf_alignment
PS2	Not assessed	Not assessed: no documented de novo proband, confirmed maternity and paternity, or PS2 point evidence is available for NM_004333.6:c.1790T>G.	cspec
PS3	Met	Met, Moderate: p.L597R increased both phospho-MEK and phospho-ERK in cells, representing two distinct VCEP-approved pathway assay types.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22798288
PS4	Not assessed	Not assessed: no verified RASopathy case-control counts, OR/RR with confidence interval, or sufficient unrelated affected probands are available to assign VCEP PS4 points.	cspec PMID:22798288 PMID:24933606 PMID:26643848 PMID:22142829
PM1	Met	Met at Moderate: residue 597 lies within the VCEP-defined CR3 activation segment, amino acids 594-627.	cspec vcep_raf_alignment
PM2	Not met	Not met: gnomAD v4.1 contains 1 allele at AF 6.20×10^-7, so the VCEP's required complete absence from gnomAD is not satisfied.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF RASopathy VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.(Leu597Arg) is a single missense substitution with no protein-length change, so it does not meet the PM4 consequence class.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no qualifying likely pathogenic alternate missense change at codon 597 is documented for the required PM5 comparison.	cspec pm5_candidates PMID:26643848 vcep_raf_alignment
PM6	Not assessed	Not assessed: no assumed-de novo observation, parental testing, phenotype documentation, or PM6 point assignment is available for NM_004333.6:c.1790T>G.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected-family segregation results are documented, below the VCEP minimum of 3 for supporting PP1.	cspec
PP2	Not assessed	Not assessed: the required BRAF gnomAD missense z score is not available for comparison with the >3.09 threshold.	cspec
PP3	Met	Met at Supporting: REVEL score 0.964 meets the BRAF VCEP missense threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the BRAF VCEP explicitly directs phenotype-specific evidence to PS4 rather than using PP4.	cspec
PP5	N/A	Not applicable: the BRAF VCEP states that PP5 is not for use under this specification.	cspec
BA1	Not met	Not met: gnomAD v4.1 total AF is 0.000062%, far below the VCEP's 0.05% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 total AF is 0.000062%, below the VCEP's 0.025% BS1 threshold.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes but provides no phenotype, age, penetrance, or VCEP point assignment for healthy individuals.	cspec gnomad_v4
BS3	N/A	Not applicable: the BRAF VCEP explicitly marks BS3 not applicable, and p.L597R increased phospho-MEK and phospho-ERK.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22798288
BS4	Not assessed	Not assessed: no affected relative lacking the variant and no informative meiosis are documented, while the VCEP requires one informative meiosis.	cspec
BP1	N/A	Not applicable: p.Leu597Arg is missense, whereas the VCEP BP1 rule is limited to specified truncating variant types.	cspec
BP2	Not assessed	Not assessed: no documented same-gene alternative pathogenic variant, phase, or qualifying alternative-cause phenotype is available to award BP2 points.	cspec PMID:22798288
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable, and p.(Leu597Arg) is a missense substitution rather than an in-frame repeat-region insertion or deletion.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.964 exceeds the BRAF VCEP BP4 missense threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no documented alternate causative variant or fully explanatory phenotype-inconsistent diagnosis is available to assign VCEP BP5 points.	cspec
BP6	N/A	Not applicable: the BRAF VCEP states that BP6 is not for use under this specification.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, noncanonical intronic, or non-coding variants, whereas this variant is missense p.(Leu597Arg).	cspec

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