Variant classification summary

NM_004333.6:c.1397G>T

BRAF · NP_004324.2:p.(Gly466Val) · NM_004333.6

GRCh37: chr7:140481411 C>A · GRCh38: chr7:140781611 C>A

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.(Gly466Val)

gnomAD AF

6.195548869869931e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: reduced BRAF kinase activity and cellular MEK/ERK pathway activation support a damaging effect.

2

PM1 moderate: p.Gly466Val lies in the VCEP-approved exon 11 P-loop domain spanning amino acids 459-474.

3

PP3 supporting: REVEL 0.781 exceeds the BRAF VCEP missense threshold of 0.7.

Final determination: Under the BRAF VCEP Version 2.3 framework, no pathogenic or benign combination rule is satisfied by PS3 Moderate, PM1 Moderate, and PP3 Supporting, so the 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: the BRAF VCEP marks PVS1 not applicable, and c.1397G>T is a missense p.(Gly466Val) substitution.	cspec
PS1	Not met	Not met: the reviewed records identify the queried G466V variant but provide no distinct previously established pathogenic same-amino-acid comparator for PS1.	cspec PMID:15035987 PMID:15046639 PMID:12068308 PMID:22649091 clinvar
PS2	Not assessed	Not assessed: no documented affected-proband de novo finding, parental testing, confirmed maternity/paternity, or VCEP-assigned PS2 points is available.	cspec
PS3	Met	Met, Moderate: two different approved assay types—reduced BRAF kinase activity and cellular MEK/ERK activation—support a damaging functional effect for p.G466V.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:15035987 PMID:22649091
PS4	Not assessed	Not assessed: the only extracted exact-variant case/control observation is somatic NSCLC versus normal DNA, without an eligible RASopathy cohort or PS4 odds ratio, confidence interval, or points.	cspec PMID:12068308
PM1	Met	Met, Moderate: residue 466 lies within the VCEP-approved exon 11 P-loop domain spanning amino acids 459-474.	cspec vcep_raf_alignment
PM2	Not met	Not met: the variant is observed in gnomAD v2.1 at 1/251426 alleles, so it is not absent from controls as required for PM2.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF VCEP explicitly designates PM3 as not applicable for this interpretation.	cspec
PM4	N/A	Not applicable: c.1397G>T changes Gly466 to Val without an in-frame indel, stop-loss event, or protein-length change.	cspec
PM5	Not met	Not met: zero collected same-residue PM5 candidates satisfy the VCEP requirement for a likely pathogenic alternate change at codon 466.	cspec pm5_candidates PMID:15046639 PMID:15035987 PMID:12068308
PM6	Not assessed	Not assessed: no documented affected-proband observation, unconfirmed parental status, or VCEP-assigned PM6 points is available for this variant.	cspec
PP1	Not assessed	Not assessed: no family segregation results or informative meiosis count is documented; the VCEP thresholds are 3, 5, and 7 informative meioses.	cspec
PP2	Not assessed	Not assessed: the required BRAF missense z score is unavailable, so comparison with the VCEP threshold of >3.09 cannot be made.	cspec gnomad_v2 gnomad_v4
PP3	Met	Met: REVEL score 0.781 exceeds the BRAF VCEP PP3 threshold of 0.7 for missense variants.	cspec revel
PP4	N/A	Not applicable: the BRAF VCEP explicitly excludes PP4 and directs phenotype-specific assessment to PS4.	cspec
PP5	N/A	Not applicable: the BRAF VCEP prohibits PP5 use, regardless of the available ClinVar or published pathogenic assertions.	cspec clinvar
BA1	Not assessed	Not assessed: the required gnomAD filtering allele frequency is unavailable, although the reported maximum unfiltered frequency is only 0.00462% versus the 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: the required gnomAD filtering allele frequency is unavailable, although the reported maximum unfiltered frequency is only 0.00462% versus the 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but provides no identified healthy carrier or VCEP point assignment required for the BS2 -4 or -1 point thresholds.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the BRAF VCEP explicitly marks BS3 as not applicable and lists BS3_NA for the approved BRAF functional assay rows.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no documented unaffected informative relative or non-segregating meiosis is available, while the VCEP requires one informative meiosis.	cspec
BP1	N/A	Not applicable: BP1 is restricted by the VCEP to specified truncating variants, whereas this variant is missense p.Gly466Val.	cspec
BP2	Not assessed	Not assessed: no same-gene alternative pathogenic variant, phase information, or qualifying RASopathy phenotype evidence is documented for the BP2 rule.	cspec
BP3	N/A	Not applicable: the BRAF VCEP marks BP3 not applicable, and c.1397G>T is a missense p.(Gly466Val) substitution.	cspec
BP4	Not met	Not met: REVEL score 0.781 is above the BRAF VCEP BP4 missense cutoff of 0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant in a different gene and no phenotype documentation showing that another variant fully explains the presentation are available.	cspec clinvar
BP6	N/A	Not applicable: the BRAF VCEP prohibits BP6 use, regardless of whether a reputable source reports the variant as benign.	cspec
BP7	N/A	Not applicable: c.1397G>T is a missense variant producing p.(Gly466Val), not a synonymous, intronic, or non-coding variant.	cspec

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