Variant classification summary

NM_001904.4:c.98C>G

CTNNB1 · NP_001895.1:p.(Ser33Cys) · NM_001904.4

GRCh37: chr3:41266101 C>G · GRCh38: chr3:41224610 C>G

Gene: CTNNB1 Transcript: NM_001904.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting BP1 supporting

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Ser33Cys)

gnomAD AF

ClinVar

other

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Supporting pathogenic evidence: p.Ser33Cys increased CTNNB1 reporter activity 5.4-fold versus vector and 3.6-fold versus wild type.

2

Moderate pathogenic evidence: CTNNB1 Ser33 is a statistically significant hotspot in the phosphorylation/degradation-targeting region.

3

Supporting pathogenic evidence: the variant is absent from gnomAD v2.1 and v4.1.

4

Supporting benign evidence: CTNNB1 disease in the relevant germline context is predominantly associated with truncating variants, not missense variants.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one moderate plus two supporting pathogenic criteria and one supporting benign criterion satisfy neither a pathogenic nor a benign combination, 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: 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.Ser33Cys is reported in tumors, but no previously established pathogenic classification for this same amino-acid change is documented.	clinvar oncokb PMID:18500270 PMID:16685513 PMID:19582367 PMID:21761366
PS2	Not assessed	Not assessed: confirmed maternity and paternity, disease status, and absence of family history are not documented for the proband.
PS3	Met	Met at supporting strength: p.Ser33Cys increased reporter activity 5.4-fold versus vector and 3.6-fold versus wild-type CTNNB1 in triplicate transfections.	PMID:19582367
PS4	Not assessed	Not assessed: exact-variant case reports lack a qualifying control comparison, so the required OR/RR >5.0 and confidence interval excluding 1.0 cannot be calculated.	PMID:18500270 PMID:16685513 PMID:19582367 PMID:21761366 PMID:26822237
PM1	Met	Met, moderate: CTNNB1 Ser33 is a statistically significant hotspot in the phosphorylation/degradation-targeting region and the variant is absent from gnomAD v2.1 and v4.1.	hotspots gnomad_v2 gnomad_v4 PMID:19582367 PMID:21761366 PMID:18500270
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, below the <=0.0001 allele-frequency threshold for PM2.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: CTNNB1-related germline disease is autosomal dominant, whereas PM3 is restricted to recessive disorders with a pathogenic variant confirmed in trans.
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 change at CTNNB1 Ser33 with a documented pathogenic determination is available in the reviewed evidence.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no assumed de novo occurrence is documented, and parental testing or family-history data are unavailable.
PP1	Not assessed	Not assessed: no affected relatives or cosegregating meioses are documented for this variant in a disease family.
PP2	Not met	Not met: CTNNB1 disease evidence is dominated by truncating loss-of-function variants, without evidence that missense disease is the common mechanism and benign missense variation is low.	pvs1_gene_context
PP3	Not met	Not met: missense REVEL score 0.453 is below the PP3 supporting threshold of >=0.644 and remains in the gray zone.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is available to determine whether the presentation is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar classifies the exact variant as "other" with zero expert-panel submissions, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the >=0.05 allele-frequency threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 reported no observations, so grpmax FAF was not >=0.01, the generic BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no phenotype-confirmed healthy adult carrying this variant was reported, so the BS2 observation requirement cannot be evaluated.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: p.Ser33Cys increased transcriptional activity 5.4-fold versus vector and 3.6-fold versus wild-type CTNNB1 rather than showing no damaging effect.	PMID:19582367
BS4	Not assessed	Not assessed: no affected relatives with documented negative variant testing are available to demonstrate lack of segregation.
BP1	Met	Met, supporting: CTNNB1 syndrome is reported to be caused predominantly by pathogenic nonsense or frameshift variants, while this variant is missense.	pvs1_gene_context
BP2	Not assessed	Not assessed: no germline pathogenic partner variant or phase result establishes c.98C>G in trans or cis, and available reports are somatic tumor observations.	PMID:16685513 PMID:18500270 PMID:19582367 PMID:21761366
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 score 0.453 exceeds the BP4 supporting threshold of <=0.29 and remains in the gray zone.	revel
BP5	Not assessed	Not assessed: no case is documented with an alternate molecular basis for disease alongside this exact variant.
BP6	Not met	Not met: ClinVar classifies the exact variant as "other" with zero expert-panel submissions, not Benign or Likely benign.	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.