Variant classification summary

NM_000633.3:c.302G>T

BCL2 · NP_000624.2:p.(Gly101Val) · NM_000633.3

GRCh37: chr18:60985598 C>A · GRCh38: chr18:63318365 C>A

Gene: BCL2 Transcript: NM_000633.3

Final call

VUS

PS3 supporting PM2 supporting

Variant details

Gene

BCL2

Transcript

NM_000633.3

Protein

NP_000624.2:p.(Gly101Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: independent functional assays showed approximately 180-fold reduced venetoclax affinity for BCL2 Gly101Val.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

3

VUS: two supporting criteria do not satisfy a generic ACMG pathogenic or benign combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, PS3 supporting plus PM2 supporting is insufficient for a pathogenic, likely pathogenic, benign, or likely benign rule, so the final 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: 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 met	Not met: p.Gly101Val is reported as an acquired venetoclax-resistance mutation, but no previously established pathogenic same-amino-acid variant is documented.	clinvar PMID:30514704 PMID:31160589
PS2	Not assessed	Not assessed: no documented disease phenotype, family-history assessment, or confirmed maternity and paternity is available to establish a de novo occurrence.
PS3	Met	Met at supporting: independent biochemical, structural, cell-line, and patient-cell assays showed approximately 180-fold reduced venetoclax affinity for BCL2 Gly101Val.	PMID:30514704 PMID:31160589
PS4	Not met	Not met: the reported 7 progression cases concern acquired venetoclax resistance, not a qualifying germline case-control comparison with OR/RR >5.0 and confidence interval excluding 1.0.	PMID:30514704 PMID:31160589
PM1	Not assessed	Not assessed: Gly101 has strong drug-binding evidence, including approximately 180-fold reduced affinity, but critical germline-domain status and regional benign variation are unestablished.	PMID:30514704 PMID:31160589 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no germline parental testing or documented pathogenic variant in trans is available to establish the required phase for a recessive disorder.
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 verified different missense substitution at BCL2 Gly101 determined to be pathogenic is documented in the available evidence.
PM6	Not assessed	Not assessed: no proband disease evidence or parental-testing record supports an assumed de novo variant without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives, variant testing results, pedigree, or meioses are documented to evaluate co-segregation.
PP2	Not assessed	Not assessed: the available evidence does not establish both PP2 requirements—low benign missense variation and a common missense disease mechanism—for BCL2.
PP3	Not met	Not met: missense REVEL 0.492 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no case-level phenotype or family-history information is available to determine whether the presentation is highly specific for a single-gene disease.	PMID:30514704 PMID:31160589
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification, and the OncoKB oncology label is not an eligible PP5 assertion.	clinvar oncokb
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF reaching 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, so no grpmax FAF reaches the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult observation or evidence of full early-age penetrance is available for the BS2 requirement.
BS3	Not met	Not met: studies showed approximately 180-fold reduced venetoclax affinity and acquired resistance rather than no damaging effect on BCL2 function or splicing.	PMID:30514704 PMID:31160589
BS4	Not assessed	Not assessed: no affected relatives lacking the variant or other family segregation data are documented to establish lack of segregation.
BP1	Not assessed	Not assessed: the available evidence does not show that primarily truncating BCL2 variants are the known disease-causing variant class.
BP2	Not assessed	Not assessed: no germline cis or trans observation with a pathogenic variant is documented for this BCL2 variant.
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	Not met	Not met: missense REVEL 0.492 is above the generic BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented to show that another molecular basis explains the disease.	PMID:30514704 PMID:31160589
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification, and available oncology evidence is not a benign assertion.	clinvar oncokb
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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