Variant classification summary

NM_004333.6:c.1406G>C

BRAF · NP_004324.2:p.(Gly469Ala) · NM_004333.6

GRCh37: chr7:140481402 C>G · GRCh38: chr7:140781602 C>G

Gene: BRAF Transcript: NM_004333.6

Final call

Likely Pathogenic

PS1 strong PS3 moderate PM1 moderate PP3 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Gly469Ala)

gnomAD AF

1.8587107238934784e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: the exact p.Gly469Ala change is recorded as pathogenic, supporting PS1 at strong.

2

Pathogenic evidence: distinct MEK- and ERK-activation assays support damaging BRAF signaling, meeting PS3 at moderate.

3

Pathogenic evidence: residue 469 lies within the VCEP-approved P-loop domain, meeting PM1 at moderate.

4

Pathogenic evidence: REVEL 0.724 exceeds the VCEP missense threshold, meeting PP3 at supporting.

Final determination: Under BRAF VCEP Rule11, one strong pathogenic criterion plus one moderate pathogenic criterion yields a Likely Pathogenic classification; PS1 strong and PM1 moderate satisfy this rule.

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 marks PVS1 Not Applicable, and c.1406G>C is a missense p.(Gly469Ala) substitution.	cspec pvs1_variant_assessment
PS1	Met	Met, Strong: ClinVar records the exact BRAF p.Gly469Ala variant as Pathogenic, supported by variant-specific functional reports, but review is warranted because submission status is single-submitter.	cspec clinvar PMID:22510884 PMID:22773810
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, confirmed maternity and paternity, or de novo point score is documented.	cspec
PS3	Met	Met at Moderate: two different approved assays, MEK and ERK activation, directly support damaging BRAF G469A gain-of-function signaling.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22510884 PMID:22773810
PS4	Not assessed	Not assessed: exact-variant literature lacks qualifying RASopathy cases or affected-control counts, so no PS4 points, odds ratio, or confidence interval can be established.	cspec PMID:14612909 PMID:22773810 PMID:22510884 PMID:24033266 PMID:12068308 PMID:20179705 gnomad_v4
PM1	Met	Met, Moderate: residue 469 lies within the VCEP-approved P-loop domain spanning amino acids 459-474, so the domain-based PM1 rule applies.	cspec vcep_raf_alignment
PM2	Not met	Not met: the variant is present in gnomAD v2.1 (1 allele) and gnomAD v4.1 (3 alleles), contrary to the VCEP PM2 absence requirement.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF VCEP explicitly designates PM3 as Not Applicable.	cspec
PM4	Not met	Not met: c.1406G>C is a missense p.(Gly469Ala) substitution and produces no protein-length change for PM4.	cspec pvs1_variant_assessment
PM5	Not met	Not met: no different likely pathogenic or pathogenic missense change at BRAF codon 469 was identified; reported G468 substitutions are at a different codon.	cspec pm5_candidates PMID:12068308 PMID:14612909
PM6	Not assessed	Not assessed: no assumed de novo observation, parental testing, or VCEP phenotype-based point assignment is documented.	cspec
PP1	Not assessed	Not assessed: 0 informative meioses are documented, below the VCEP's minimum of 3 for supporting strength.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a gnomAD missense z score above 3.09, but no missense z score is available for BRAF.	cspec gnomad_v2 gnomad_v4
PP3	Met	Met at Supporting: the missense REVEL score is 0.724, meeting the VCEP threshold of ≥0.7.	cspec revel
PP4	N/A	Not applicable: the BRAF RASopathy VCEP explicitly directs phenotype-specific evidence to PS4 instead of PP4.	cspec
PP5	N/A	Not applicable: the VCEP prohibits PP5, regardless of pathogenic assertions reported for this variant.	cspec
BA1	Not met	Not met: maximum observed gnomAD frequency is 0.00289%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum observed gnomAD frequency is 0.00289%, below the VCEP BS1 threshold of 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but the VCEP provides no rule mapping this observation to its −4 or −1 BS2 point options.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the BRAF VCEP explicitly designates BS3 as not applicable, and variant-specific assays show damaging signaling rather than normal function.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22510884 PMID:22773810
BS4	Not assessed	Not assessed: no affected relative or informative meiosis is documented to demonstrate lack of segregation.	cspec
BP1	N/A	Not applicable: BP1 is restricted to truncating variants, whereas BRAF c.1406G>C is a missense substitution producing p.Gly469Ala.	cspec
BP2	Not assessed	Not assessed: no documented cis/trans phase observation is available to establish the VCEP's minimum BP2 threshold of ≥ (-1) Point.	cspec
BP3	N/A	Not applicable: the VCEP explicitly marks BP3 Not Applicable in the BRAF v2.3 specification.	cspec
BP4	Not met	Not met: the missense REVEL score is 0.724, exceeding the VCEP BP4 threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or fully explained non-RASopathy phenotype is documented, so BP5 point scoring cannot be performed.	cspec clinvar
BP6	N/A	Not applicable: the VCEP prohibits BP6, regardless of any benign assertion from a reputable source.	cspec
BP7	N/A	Not applicable: this is a missense coding variant, whereas VCEP BP7 covers synonymous, eligible intronic, or non-coding variants.	cspec

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