Variant classification summary

NM_004333.6:c.1801A>G

BRAF · NP_004324.2:p.(Lys601Glu) · NM_004333.6

GRCh37: chr7:140453134 T>C · GRCh38: chr7:140753334 T>C

Gene: BRAF Transcript: NM_004333.6

Final call

VUS

PM1 moderate PP3 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Lys601Glu)

gnomAD AF

6.200073904880946e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 Moderate: Lys601 lies within the VCEP-approved CR3 activation segment at residues 594-627.

2

PP3 Supporting: REVEL 0.916 exceeds the VCEP missense threshold of 0.7.

Final determination: Under the BRAF VCEP v2.3 criteria-combination framework, PM1 at Moderate plus PP3 at Supporting does not satisfy a pathogenic or benign rule, leaving the variant as 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.1801A>G is a missense p.Lys601Glu substitution rather than a listed null variant.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: K601E is reported clinically, but no independently established pathogenic comparator was available to satisfy the VCEP's PS1 requirement.	cspec PMID:22608338
PS2	Not assessed	Not assessed: no documented germline de novo event with confirmed maternity and paternity, phenotype, and family-history information is available.	cspec
PS3	Not assessed	Not assessed: no qualifying approved functional assay result is reported for BRAF c.1801A>G/p.K601E in the governing VCEP functional-studies file.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22608338
PS4	Not assessed	Not assessed: available reports are somatic cancer observations without germline RASopathy case-control counts or a VCEP PS4 point assignment.	cspec PMID:12198537 PMID:22608338 gnomad_v4
PM1	Met	Met, Moderate: residue 601 falls within the VCEP-approved CR3 activation segment spanning residues 594-627.	cspec vcep_raf_alignment
PM2	Not met	Not met: the variant is present in gnomAD v2.1 and v4.1 at 1 observed allele in each dataset, rather than absent from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF VCEP explicitly marks PM3 as not applicable.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame indel or stop-loss, whereas c.1801A>G is a missense p.Lys601Glu substitution with no protein-length change.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no same-codon comparator variant was available to meet the VCEP's one-change or two-change PM5 thresholds.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no germline presumed-de-novo observation, parental testing, or documented RASopathy phenotype is available for point assignment.	cspec
PP1	Not assessed	Not assessed: zero informative meioses or affected-family-member segregation observations are documented for this variant.	cspec
PP2	Not assessed	Not assessed: the required BRAF missense z score is unavailable, so the VCEP threshold of >3.09 cannot be evaluated.	cspec
PP3	Met	Met: VCEP REVEL score 0.916 is above the 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 states that PP5 is not for use.	cspec
BA1	Not met	Not met: the highest observed gnomAD population frequency is 0.00398%, below the VCEP BA1 threshold of 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed gnomAD population frequency is 0.00398%, 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 converting that observation into the required BS2 points.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the BRAF VCEP explicitly designates BS3 as not applicable and the approved assay table assigns BS3_NA.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis demonstrates lack of segregation in an affected family member.	cspec
BP1	N/A	Not applicable: c.1801A>G is a missense variant, while this VCEP restricts BP1 to specified truncating variant types.	cspec
BP2	Not assessed	Not assessed: no phase, cis/trans, or affected-proband allelic observation establishes the VCEP's required BP2 threshold of ≥ (-1) point.	cspec
BP3	N/A	Not applicable: the BRAF VCEP marks BP3 not applicable, and p.Lys601Glu is a missense substitution rather than an in-frame indel in a benign repetitive region.	cspec pvs1_variant_assessment
BP4	Not met	Not met: VCEP REVEL score 0.916 exceeds the BP4 missense threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative germline variant or VCEP BP5 point assignment is documented for a RASopathy phenotype.	cspec
BP6	N/A	Not applicable: the BRAF VCEP states that BP6 is not for use.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, intronic, or non-coding variants, not this missense variant.	cspec

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