Variant classification summary

NM_004656.4:c.1120G>A

BAP1 · NP_004647.1:p.(Glu374Lys) · NM_004656.4

GRCh37: chr3:52438599 C>T · GRCh38: chr3:52404583 C>T

Gene: BAP1 Transcript: NM_004656.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Glu374Lys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from available gnomAD datasets.

2

BP4 supporting: the missense REVEL score is 0.202, below the generic BP4 threshold of 0.29.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion plus one supporting benign criterion does not satisfy any definitive classification threshold and therefore yields 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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously established pathogenic BAP1 variant with the same p.Glu374Lys amino-acid change is documented.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype, parental maternity/paternity confirmation, or family-history evidence establishes a de novo variant.
PS3	Not assessed	Not assessed: no variant-specific functional assay or validated evidence supporting a damaging effect was reported for BAP1 p.Glu374Lys.
PS4	Not assessed	Not assessed: no affected-versus-control prevalence, odds ratio, relative risk, or confidence interval is available for this variant.	PMID:25394175
PM1	Not assessed	Not assessed: no authoritative complete BAP1 domain table or qualifying hotspot/domain evidence is supplied for evaluating PM1.
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: BAP1 tumor predisposition syndrome is autosomal dominant, whereas PM3 requires a pathogenic variant in trans for a recessive disorder.	pvs1_gene_context
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense variant at BAP1 residue 374 has been determined pathogenic in the supplied evidence.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no affected proband or parental testing shows an assumed de novo variant without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives, variant results, phenotype assessments, or informative meioses are documented for co-segregation.
PP2	Not assessed	Not assessed: variant absence from gnomAD does not establish BAP1's gene-level benign-missense rate or a common missense disease mechanism.	gnomad_v2 gnomad_v4 gnomad_canada
PP3	Not met	Not met: missense REVEL score 0.202 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history description is available to establish a highly specific single-gene disease presentation.	PMID:25394175
PP5	Not met	Not met: ClinVar reports this exact variant as uncertain significance, with zero expert-panel submissions and no Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0 versus the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no evidence documents the variant in a healthy adult homozygote, heterozygote, or hemizygote.
BS3	Not assessed	Not assessed: no variant-specific functional assay or validated evidence showing no damaging effect on BAP1 p.Glu374Lys was reported.
BS4	Not assessed	Not assessed: no tested affected relatives are documented as lacking the variant, so lack of segregation cannot be established.
BP1	Not assessed	Not assessed: BAP1 loss-of-function is supported, but the supplied evidence does not establish a primarily truncating disease-variant spectrum.	pvs1_gene_context
BP2	Not assessed	Not assessed: no pathogenic second variant or cis/trans phase result is documented for the required BP2 observation.	pvs1_gene_context
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting: missense REVEL score 0.202 is at or below the generic BP4 threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case report documents this exact variant together with an alternate molecular basis for the disease.	clinvar
BP6	Not met	Not met: ClinVar reports this exact variant as uncertain significance, with zero expert-panel submissions and no Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.