Variant classification summary

NM_001903.5:c.710A>G

CTNNA1 · NP_001894.2:p.(Tyr237Cys) · NM_001903.5

GRCh37: chr5:138160340 A>G · GRCh38: chr5:138824651 A>G

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

PM2 supporting

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(Tyr237Cys)

gnomAD AF

4.832360459396401e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 allele frequency 4.83e-05, below the 0.1% rare-variant threshold.

2

Overall classification: VUS - a single supporting pathogenic criterion (PM2) does not meet the ACMG/AMP combination threshold for a likely pathogenic or pathogenic call.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion alone does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination; the result 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.710A>G is a missense change (p.Tyr237Cys), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no confirmed pathogenic variant producing the same p.Tyr237Cys amino-acid change was available for comparison.
PS2	Not assessed	Not assessed: no de novo observation or parental testing was available to confirm the variant arose anew.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no validated functional assay measuring the effect of p.Tyr237Cys was available.
PS4	Not assessed	Not assessed: no case-control or statistically supported enrichment data link c.710A>G to disease.	generic_acmg_combination_rules PMID:25394175 PMID:25741868 PMID:28492532 PMID:34043773 clinvar oncokb
PM1	Not assessed	Not assessed: no validated functional domain or residue-level hotspot evidence covers Tyr237 in CTNNA1.
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 4.83e-05 is well below the 0.1% rare-variant threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic CTNNA1 variant or phasing information was available.
PM4	N/A	Not applicable: c.710A>G is a missense change (p.Tyr237Cys) that does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no confirmed pathogenic missense variant at residue 237 was available as a comparator.	pm5_candidates
PM6	Not assessed	Not assessed: no report of this variant as apparently de novo without parental confirmation was available.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no affected relatives carrying the variant and no informative meioses were documented.	generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no evidence established that missense changes are a common CTNNA1 disease mechanism.
PP3	Not met	Not met: REVEL 0.278 falls below the >0.750 threshold for computational support of pathogenicity.	revel
PP4	Not assessed	Not assessed: no proband phenotype or disease-specific clinical information was provided for the carrier.	generic_acmg_combination_rules
PP5	Not met	Not met: the ClinVar record has no expert-panel submission classified pathogenic or likely pathogenic.	clinvar
BA1	Not met	Not met: the highest observed population frequency, 3.47e-04, is far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest observed population frequency, 3.47e-04, remains below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD reports zero homozygotes and no phenotype-confirmed healthy adult observations.	gnomad_v4 gnomad_v2 PMID:25741868
BS3	Not assessed	Not assessed: no validated functional assay showing preserved CTNNA1 function was available.
BS4	Not assessed	Not assessed: no affected relatives lacking the variant were documented, so segregation could not be evaluated.	generic_acmg_combination_rules
BP1	Not assessed	Not assessed: no validated gene-level evidence established that CTNNA1 disease variation is primarily truncating.
BP2	Not assessed	Not assessed: no observation of this variant in trans or in cis with a pathogenic variant was available.
BP3	N/A	Not applicable: c.710A>G is a missense change (p.Tyr237Cys), not an in-frame insertion or deletion in a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.278 is above the <0.250 BP4 threshold and falls in the 0.250-0.750 gray zone.	revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis explaining the reported phenotype was supplied.	generic_acmg_combination_rules
BP6	Not met	Not met: the ClinVar record has no expert-panel submission classified benign or likely benign.	clinvar
BP7	N/A	Not applicable: c.710A>G alters the encoded protein (p.Tyr237Cys), so the silent-variant premise does not hold.	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.