Variant classification summary

NM_004333.6:c.1742A>G

BRAF · NP_004324.2:p.(Asn581Ser) · NM_004333.6

GRCh37: chr7:140453193 T>C · GRCh38: chr7:140753393 T>C

Gene: BRAF Transcript: NM_004333.6

Final call

VUS

PS3 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Asn581Ser)

gnomAD AF

1.270807890700355e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: one approved BRAF kinase assay showed approximately six-fold higher basal activity for the N581S-equivalent mutant than wild type.

Final determination: Under the BRAF VCEP Version 2.3 combination framework, PS3 supporting alone does not satisfy a pathogenic or benign rule, so the final call 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: c.1742A>G is a missense p.Asn581Ser substitution, not a VCEP-listed null variant class.	cspec pvs1_variant_assessment
PS1	Not met	Not met: no distinct previously established pathogenic variant with the same Asn581Ser amino-acid change was identified.	cspec PMID:15035987
PS2	Not assessed	Not assessed: no documented proband-level de novo result or confirmed parental testing permits assignment of the VCEP's PS2 points.	cspec
PS3	Met	Met at Supporting: one approved BRAF kinase assay found approximately six-fold higher basal activity for the N581S-equivalent mutant than wild-type.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:15035987
PS4	Not assessed	Not assessed: no RASopathy case-control counts or point-scored affected-patient evidence are available for calculating PS4 strength.	cspec PMID:26498038 PMID:23619274 PMID:24033266 PMID:24627688
PM1	Not met	Not met: residue 581 lies outside the VCEP-listed P-loop 459-474 and CR3 activation segment 594-627 domains.	cspec vcep_raf_alignment
PM2	Not met	Not met: gnomAD v4.1 contains 2 of 1,573,802 alleles (AF 1.27081e-06), so the variant is not absent from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF RASopathy VCEP explicitly marks PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	Not met	Not met: p.Asn581Ser is a missense substitution with no in-frame insertion, deletion, stop-loss event, or protein-length change.	cspec pvs1_variant_assessment
PM5	Not met	Not met: zero qualifying likely pathogenic alternate residue changes at BRAF codon 581 were identified for the VCEP's PM5 threshold.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no documented presumed-de novo observation with parental or proband evidence permits assignment of the VCEP's PM6 points.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP's PP1 thresholds can be evaluated.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a gnomAD missense z score >3.09, but no missense z score is available.	cspec gnomad_v4
PP3	Not met	Not met: REVEL 0.666 is below the VCEP PP3 missense threshold of 0.7.	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 explicitly prohibits PP5 regardless of available literature or database assertions.	cspec PMID:23619274 PMID:24627688
BA1	Not met	Not met: gnomAD v4.1 filtering allele frequency is 0.00013%, below the VCEP's 0.05% threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 filtering allele frequency is 0.00013%, below the VCEP's 0.025% threshold.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but the VCEP's -1/-4-point requirement cannot be assigned from this dataset.	cspec gnomad_v4
BS3	N/A	Not applicable: the BRAF VCEP explicitly marks BS3 as Not applicable, regardless of the available functional assay result.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis demonstrating non-segregation is documented for evaluation against the VCEP's BS4 requirement.	cspec
BP1	N/A	Not applicable: c.1742A>G p.Asn581Ser is missense, whereas the VCEP BP1 rule names only truncating variant types.	cspec
BP2	Not assessed	Not assessed: no documented germline same-gene alternative cause, phase, or phenotype is available to establish the required threshold of ≥ (-1) point.	cspec
BP3	N/A	Not applicable: the BRAF VCEP marks BP3 not applicable, and c.1742A>G is a missense substitution rather than an in-frame indel.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.666 exceeds the VCEP BP4 missense cutoff of 0.3.	cspec revel
BP5	Not assessed	Not assessed: no documented alternate causative variant and no VCEP BP5 point value establish an alternative explanation for a RASopathy phenotype.	cspec PMID:26498038
BP6	N/A	Not applicable: the BRAF VCEP explicitly prohibits BP6 regardless of available benign-source assertions.	cspec
BP7	N/A	Not applicable: c.1742A>G is a missense variant, whereas the VCEP BP7 rule covers synonymous, intronic, or non-coding variants.	cspec

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