Variant classification summary

NM_002661.5:c.1993C>T

PLCG2 · NP_002652.2:p.(Arg665Trp) · NM_002661.5

GRCh37: chr16:81946260 C>T · GRCh38: chr16:81912655 C>T

Gene: PLCG2 Transcript: NM_002661.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

PLCG2

Transcript

NM_002661.5

Protein

NP_002652.2:p.(Arg665Trp)

gnomAD AF

1.2399994048002858e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: independent cellular assays showed enhanced PLCG2 signaling and a hypermorphic effect.

2

PM2 supporting: gnomAD v4.1 grpmax FAF is 2.8e-07 with zero homozygotes.

3

PP3 supporting: REVEL 0.746 exceeds the generic missense threshold of 0.644.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria yields Likely Pathogenic.

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.Arg665Trp was reported as a somatically acquired CLL-resistance mutation, not as a previously established pathogenic variant.	PMID:24869598 PMID:25972157
PS2	Not assessed	Not assessed: no documented germline proband-parent testing or confirmed maternity and paternity establishes a de novo variant in an affected patient.	PMID:24869598 PMID:25972157
PS3	Met	Met, strong: independent cellular assays showed enhanced calcium, IP3, ERK/AKT, and BTK-independent signaling for PLCG2 p.Arg665Trp.	PMID:24869598 PMID:25972157
PS4	Not assessed	Not assessed: variant-specific studies report somatic relapse cases but provide no comparable affected-versus-control counts or OR with a 95% confidence interval.	PMID:24869598 PMID:25972157 gnomad_v4
PM1	Not assessed	Not assessed: Cancer Hotspots found no PLCG2 R665 hotspot, and no authoritative critical-domain or benign-variation assessment covers residue 665.	hotspots cosmic
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 2.8e-07, below the 0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected germline proband, second pathogenic allele, or parental/offspring phase testing is documented for NM_002661.5:c.1993C>T.
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: the available evidence reports p.Arg665Trp itself but identifies no different missense variant at Arg665 determined to be pathogenic.	PMID:24869598 PMID:25972157 pm5_candidates
PM6	Not assessed	Not assessed: no affected-patient and assumed-germline de novo observation is documented, and parental genotype information is unavailable.	PMID:24869598 PMID:25972157
PP1	Not assessed	Not assessed: zero informative affected relatives or meioses are documented to demonstrate cosegregation of the variant with disease.
PP2	Not assessed	Not assessed: no gene-level benign-missense rate and no validated evidence that missense variants are a common PLCG2 disease mechanism are supplied.
PP3	Met	Met at supporting: REVEL 0.746 exceeds the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided that is highly specific for a single-gene disease caused by this variant.	PMID:24869598 PMID:25972157 clinvar
PP5	Not met	Not met: ClinVar records one single-submitter uncertain-significance assertion and no exact-variant expert-panel pathogenic or likely pathogenic classification.	clinvar oncokb
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, far below the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 2.8e-07, far below the generic 0.01 BS1 threshold.	gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult germline observation is documented, and the available R665W reports describe somatic cancer relapse samples.	PMID:24869598 PMID:25972157
BS3	Not assessed	Not assessed: no validated functional study shows that PLCG2 p.Arg665Trp has no damaging effect on protein function or splicing.	PMID:24869598 PMID:25972157
BS4	Not assessed	Not assessed: no affected relatives are documented with reliable genotype results showing absence of the variant.
BP1	Not assessed	Not assessed: no gene-wide evidence shows that PLCG2 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no phase-resolved germline observation shows this variant in trans or cis with a pathogenic variant under the BP2 conditions.
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: REVEL 0.746 is above the generic BP4 supporting cutoff of 0.29 for this missense variant.	revel
BP5	Not met	Not met: a relapse patient had R665W with BTK C481S, but the somatic resistance report does not establish an alternate molecular basis for the queried germline disease.	PMID:24869598 PMID:25972157
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification, only a single-submitter uncertain-significance 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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