Variant classification summary

NM_004333.6:c.1798_1799delinsAA

BRAF · NP_004324.2:p.(Val600Lys) · NM_004333.6

GRCh37: chr7:140453136 AC>TT · GRCh38: chr7:140753336 AC>TT

Gene: BRAF Transcript: NM_004333.6

Final call

VUS

PS3 moderate PM1 moderate PM2 supporting

Variant details

Gene

BRAF

Transcript

NM_004333.6

Protein

NP_004324.2:p.(Val600Lys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 moderate: BRAF V600K activated both MEK and ERK in approved functional assays.

2

PM1 moderate: residue 600 is within the VCEP-approved CR3 activation segment.

3

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1 all-comers datasets.

Final determination: Under the BRAF VCEP Version 2.3 combination rules, PS3 moderate plus PM1 moderate and PM2 supporting does not meet any pathogenic or benign rule, 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: c.1798_1799delinsAA is a missense p.(Val600Lys) change, not a VCEP-listed null variant such as a nonsense, frameshift, or canonical splice variant.	cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: p.Val600Lys is reported as ClinVar uncertain significance, with no demonstrated previously established pathogenic same-amino-acid comparator.	cspec clinvar PMID:26343582 vcep_raf_alignment
PS2	Not assessed	Not assessed: no documented proband phenotype, confirmed maternity and paternity, absence of family history, or parental testing is available for de novo scoring.	cspec
PS3	Met	Met at Moderate: BRAF V600K activated both MEK and ERK, satisfying the VCEP rule that two different approved assays support Moderate PS3.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:26343582
PS4	Not assessed	Not assessed: the VCEP requires phenotype point scoring, but no affected-case/control counts or VCEP PS4 point assignment are available.	cspec PMID:26343582
PM1	Met	Met, Moderate: residue 600 falls within the VCEP-approved CR3 activation segment domain spanning amino acids 594-627.	cspec vcep_raf_alignment
PM2	Met	Met, supporting: the variant is absent from both default all-comers gnomAD v2.1 and v4.1 control datasets.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the BRAF VCEP explicitly marks PM3 as not applicable for this RASopathy framework.	cspec
PM4	Not met	Not met: the two-nucleotide delins produces missense p.(Val600Lys) without a protein-length change or stop-loss consequence, despite BRAF having no known repetitive areas.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: the PM5 search found zero same-residue comparator candidates meeting the VCEP's likely-pathogenic comparator requirement.	cspec pm5_candidates
PM6	Not assessed	Not assessed: parental testing, de novo status, and the phenotype information required to choose among 2, 1, or 0.5 PM6 points are unavailable.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so none of the VCEP thresholds of at least 3, 5, or 7 meioses can be evaluated.	cspec
PP2	Not assessed	Not assessed: the required BRAF missense z score is unavailable, so comparison with the VCEP threshold >3.09 cannot be performed.	cspec gnomad_v2 gnomad_v4
PP3	Not assessed	Not assessed: the missense PP3 path requires REVEL >=0.7, but no REVEL score is available for p.(Val600Lys).	cspec
PP4	N/A	Not applicable: the BRAF VCEP explicitly directs PP4 to PS4 instead of allowing an independent PP4 assertion.	cspec
PP5	N/A	Not applicable: the BRAF VCEP prohibits PP5 use under its governing specification, regardless of literature classification.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's ≥0.05% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the VCEP's ≥0.025% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy-individual or homozygote evidence is available to assign the VCEP's -4-point or -1-point BS2 rule.
BS3	N/A	Not applicable: the BRAF VCEP explicitly designates BS3 as not applicable, regardless of the available functional assay results.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected family member with variant testing or one informative meiosis demonstrating non-segregation is documented.	cspec
BP1	N/A	Not applicable: p.Val600Lys is missense, whereas the VCEP BP1 rule applies only to specified truncating variant classes.	cspec
BP2	Not assessed	Not assessed: no documented second pathogenic BRAF variant, phase relationship, or VCEP BP2 point assignment is available to evaluate the ≥ (-1) Point threshold.	cspec
BP3	N/A	Not applicable: the BRAF VCEP explicitly excludes BP3, whose general definition concerns in-frame indels in benign repetitive regions without known function.	cspec
BP4	Not assessed	Not assessed: the missense BP4 path requires REVEL <=0.3, but no REVEL score is available for p.(Val600Lys).	cspec
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point total is available to establish an alternate molecular explanation.	cspec
BP6	N/A	Not applicable: the BRAF VCEP prohibits BP6 use under its governing specification, regardless of benign literature reports.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous, noncanonical intronic, or non-coding variants, whereas this variant is missense p.(Val600Lys).	cspec

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