CTNNA1 c.*17C>T, p.(=)

Reasoning

No applicable CTNNA1 VCEP or gene-specific framework was identified, so the supplied generic PM2 threshold of allele frequency <=0.0001 was applied. The all-comers gnomAD v4.1 allele frequency is 0.000237126 (379/1,598,306 alleles), above 0.0001; gnomAD v2.1 non-cancer exomes report 0.000309267 (70/226,342 alleles), also above the threshold. The variant is therefore too frequent for generic PM2.

Rule

Generic ACMG/ClinGen-SVI PM2: allele frequency <=0.0001; no applicable gene-specific specification.

Evidence considered

• No CTNNA1-specific VCEP specification was available; the supplied generic ACMG/ClinGen-SVI PM2 threshold is allele frequency <=0.0001.
• gnomAD v4.1 reports an all-comers allele frequency of 0.000237126 (379/1,598,306 alleles) and one homozygote.
• The specified non-cancer exome subset in gnomAD v2.1 reports 0.000309267 (70/226,342 alleles), which is also above the PM2 threshold.

Sources

Reasoning

No applicable CTNNA1 VCEP or gene-specific framework was identified, so the supplied generic ACMG/AMP BA1 threshold of allele frequency >=0.05 was applied. The highest reported population frequency is 0.00421782 as the gnomAD v4.1 exome group maximum, while the all-comers gnomAD v4.1 allele frequency is 0.000237126 (379/1,598,306 alleles); gnomAD v2.1 non-cancer exomes show 0.000309267 (70/226,342 alleles). These values are all below 0.05, so BA1 is not met.

Rule

Generic ACMG/AMP BA1: allele frequency >=0.05; no applicable gene-specific specification.

Evidence considered

• No CTNNA1-specific VCEP specification was available; the supplied generic ACMG/AMP BA1 threshold is allele frequency >=0.05.
• gnomAD v4.1 reports an all-comers allele frequency of 0.000237126 (379/1,598,306 alleles), an exome group maximum frequency of 0.00421782, and an African/African American frequency of 0.00400708.
• gnomAD v2.1 non-cancer exomes report an allele frequency of 0.000309267 (70/226,342 alleles), also below the BA1 threshold.

Sources

Reasoning

No applicable CTNNA1 VCEP or gene-specific framework was identified, so the supplied generic BS1 threshold of allele frequency >=0.01 was applied. The highest robust group-level frequency is 0.00421782 in gnomAD v4.1 exomes, below 0.01; the gnomAD v4.1 all-comers frequency is 0.000237126. gnomAD v2.1 non-cancer exomes report 0.000309267, and the gnomAD v3.1 non-cancer genome-wide frequency is 0.000974725 with a 0.00290567 group maximum. A single HGDP:YORUBA observation of 1/38 alleles (0.0263158) is an unstable tiny-subgroup estimate and does not establish a general population frequency exceeding the threshold. BS1 is therefore not met.

Rule

Generic ACMG/AMP BS1: allele frequency >=0.01; no applicable gene-specific specification.

Evidence considered

• No CTNNA1-specific VCEP specification was available; the supplied generic ACMG/AMP BS1 threshold is allele frequency >=0.01.
• gnomAD v4.1 reports an exome group maximum frequency of 0.00421782 and an all-comers allele frequency of 0.000237126.
• The non-cancer subsets report 0.000309267 in gnomAD v2.1 exomes and 0.000974725 overall with a 0.00290567 group maximum in gnomAD v3.1 genomes.
• The gnomAD v3.1 HGDP:YORUBA value of 0.0263158 is based on 1 of 38 alleles and is treated as a small-sample subgroup artifact rather than a representative population frequency.

Sources

Reasoning

Generic ACMG/AMP PS2 requires a de novo variant in an affected proband with confirmed maternity and paternity, with phenotype consistency supporting causality. The case evidence does not document a proband, parental genotypes, maternity/paternity confirmation, phenotype assessment, or a de novo observation; therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: confirmed de novo occurrence in an affected individual, with confirmed maternity and paternity and a consistent phenotype; strength is not assigned without those observations.

Evidence considered

• The case evidence does not provide proband-level clinical details or parental testing results for NM_001903.5:c.*17C>T.
• No documented maternity/paternity confirmation or de novo status is available.
• No applicable CTNNA1-specific VCEP/CSPEC specification was retrieved; generic ACMG/AMP criteria are used.

Still missing

• Affected proband identification and phenotype details
• Maternal and paternal testing results for NM_001903.5:c.*17C>T
• Maternity and paternity confirmation
• Assessment of phenotype consistency with a CTNNA1-related disorder

Reasoning

No variant-specific functional assay evidence was identified for NM_001903.5:c.*17C>T (CTNNA1), a downstream 3′-UTR variant predicted to have no protein change. The reviewed literature contains no report of this exact variant in a validated assay with appropriate controls, a disease-relevant readout, or a calibrated threshold supporting pathogenic functional impact. Therefore PS3 cannot be applied at any strength.

Evidence considered

• The variant is NM_001903.5:c.*17C>T in the downstream 3′-UTR of CTNNA1 and is annotated as NP_001894.2:p.(=), so no protein-altering functional result can be assumed.
• The reviewed exact-variant literature extraction found no report of this variant in a functional assay, and the available CTNNA1 guideline paper reports clinical background rather than variant-specific experimental data.

Still missing

• A validated assay testing the exact variant is not available.
• Assay controls, biological relevance, quantitative results, and a published PS3 strength calibration are unavailable for this variant.

Sources

Reasoning

No case-control study, affected-case enrichment analysis, odds ratio, or statistically supported excess of this exact CTNNA1 variant in affected individuals versus controls was identified. The available literature consists of general cancer-risk guidance or gene-level discussion and does not provide variant-specific prevalence data. Therefore PS4 cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires a statistically significant increased prevalence of the variant in affected individuals compared with controls; no variant-specific enrichment statistic was available.

Evidence considered

• The reviewed clinical guideline states that pathogenic CTNNA1 variants occur in a minority of hereditary diffuse gastric cancer families but does not report NM_001903.5:c.*17C>T or a case-control comparison for it.
• The reviewed cancer-genetics policy statement and referral guideline provide no CTNNA1 c.*17C>T-specific affected-case or control counts, enrichment statistic, or odds ratio.

Still missing

• Variant-specific case-control or affected-case enrichment data are unavailable.

Sources

Reasoning

Generic ACMG/AMP PM6 applies when a variant is reported as de novo but maternity and/or paternity has not been confirmed. The case evidence contains no report of a de novo event, affected proband, parental genotypes, or family testing, so PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence in an affected individual when maternity and/or paternity has not been confirmed; strength is not assigned without a documented de novo observation.

Evidence considered

• No de novo observation for NM_001903.5:c.*17C>T is documented in the case evidence.
• No parental genotypes or parentage-confirmation information is provided.
• No applicable CTNNA1-specific VCEP/CSPEC specification was retrieved; generic ACMG/AMP criteria are used.

Still missing

• Reported de novo status for the variant
• Affected proband identification and phenotype details
• Parental genotype results
• Maternity and paternity confirmation status

Reasoning

Generic ACMG/AMP PP1 requires cosegregation of the variant with disease in affected family members, with evidentiary strength informed by the number and informativeness of meioses. The case evidence provides no pedigree, affected relatives, variant genotypes, phenotypes, or meiosis count; therefore PP1 cannot be assessed.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in affected family members; strength depends on the quantity and informativeness of observed meioses.

Evidence considered

• The case evidence contains no family pedigree or affected-relative information.
• No familial genotype data, phenotype concordance data, or informative meioses are reported for NM_001903.5:c.*17C>T.
• No applicable CTNNA1-specific VCEP/CSPEC specification was retrieved; generic ACMG/AMP criteria are used.

Still missing

• Pedigree and relationship information
• Phenotypes and disease status of relatives
• Variant genotypes for affected and unaffected relatives
• Number of informative meioses and segregation analysis

Reasoning

The available records do not provide a documented phenotype for a proband carrying NM_001903.5:c.*17C>T, nor do they establish that any phenotype is highly specific for a CTNNA1-related disorder. Gene-level statements about hereditary diffuse gastric cancer and lobular breast cancer are not sufficient to apply PP4 to this exact variant and individual.

Rule

Generic ACMG/AMP PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single-gene etiology; gene-level disease descriptions without an exact-variant case phenotype are insufficient.

Evidence considered

• The guideline discusses hereditary diffuse gastric cancer and lobular breast cancer in carriers of pathogenic CTNNA1 variants, but explicitly addresses gene-level disease context and does not report this exact variant or a case phenotype.
• No case summary or literature extraction documents a highly specific CTNNA1-related phenotype in a carrier of NM_001903.5:c.*17C>T.

Still missing

• A detailed phenotype for an individual carrying the exact variant is unavailable.
• Phenotype specificity for CTNNA1-related disease has not been established for this case.

Sources

Reasoning

PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The available ClinVar record is not an exact match: it describes NM_001903.5(CTNNA1):c.2472C>T (p.Asn824=), reports criteria provided by single submitters, and contains zero expert-panel submissions. The ordinary laboratory submissions and aggregate labels therefore cannot trigger PP5.

Rule

Apply PP5 only when an exact-variant ClinVar expert-panel assertion classifies the variant as Pathogenic or Likely pathogenic; non-expert or non-exact records do not qualify.

Evidence considered

• ClinVar variation 1109167 was not an exact match; its title is NM_001903.5(CTNNA1):c.2472C>T (p.Asn824=), while the reviewed variant is NM_001903.5:c.*17C>T.
• The ClinVar submission audit reports review status criteria provided, single submitter, expert-panel submissions 0, and no usable exact-variant submissions.
• Under the requested rule, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger PP5.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available.

Sources

Reasoning

gnomAD v4.1 reports one homozygote among 1,598,306 alleles, while gnomAD v2.1 reports no homozygotes. However, these population databases do not establish that the homozygous individual is a clinically evaluated, unaffected adult with appropriate ascertainment, and CTNNA1-related disease penetrance is not established as complete. The available data therefore do not support applying BS2, but they are insufficient to make a definitive benign-evidence determination without phenotype and age information.

Rule

Generic ACMG/AMP BS2 requires observation in healthy adults for a fully penetrant dominant disorder or homozygotes for a fully penetrant recessive disorder; available data do not establish these conditions.

Evidence considered

• gnomAD v4.1 reports homozygotes = 1; gnomAD v2.1 reports homozygotes = 0.
• The gnomAD counts do not by themselves document that the homozygote was an unaffected adult or provide the clinical ascertainment needed for BS2.
• The reviewed CTNNA1 hereditary diffuse gastric cancer guideline states that the penetrance of pathogenic CTNNA1 variants remains poorly characterized, preventing an assumption of complete penetrance.

Still missing

• No individual-level age, phenotype, cancer history, or clinical ascertainment data are available for the gnomAD v4.1 homozygote.
• Complete penetrance of the relevant CTNNA1-associated disorder has not been established.

Sources

Reasoning

No variant-specific functional assay evidence was identified for NM_001903.5:c.*17C>T (CTNNA1), a downstream 3′-UTR variant predicted to have no protein change. The reviewed literature contains no report of this exact variant in a validated assay with appropriate controls, a disease-relevant readout, or a calibrated threshold supporting a benign functional effect. Therefore BS3 cannot be applied at any strength.

Evidence considered

• The variant is NM_001903.5:c.*17C>T in the downstream 3′-UTR of CTNNA1 and is annotated as NP_001894.2:p.(=), so absence of a protein change does not establish a benign functional effect.
• The reviewed exact-variant literature extraction found no report of this variant in a functional assay, and the available CTNNA1 guideline paper reports clinical background rather than variant-specific experimental data.

Still missing

• A validated assay testing the exact variant is not available.
• Assay controls, biological relevance, quantitative results, and a published BS3 strength calibration are unavailable for this variant.

Sources

Reasoning

Generic ACMG/AMP BS4 requires lack of segregation with disease in affected family members, interpreted using reliable phenotyping and informative family genotypes. The case evidence contains no affected relatives, family genotypes, phenotype assessments, or segregation analysis; absence of those data cannot establish non-segregation, so BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation with disease in affected family members, requiring reliable phenotyping and informative familial genotypes.

Evidence considered

• The case evidence does not document affected relatives or their phenotypes.
• No familial genotype results or non-segregation analysis are available for NM_001903.5:c.*17C>T.
• No applicable CTNNA1-specific VCEP/CSPEC specification was retrieved; generic ACMG/AMP criteria are used.

Still missing

• Pedigree and relationship information
• Reliable disease phenotyping of relatives
• Variant genotypes for affected relatives
• Documented non-segregation analysis

Reasoning

No applicable CTNNA1 gene-specific framework was available, so generic ACMG/AMP logic was used. BP2 requires a documented allelic relationship, such as observation of the variant in trans with a pathogenic variant in a dominant disorder or in cis with a pathogenic variant in a recessive disorder. The available case evidence contains no affected-proband data, second-variant identity, pedigree, segregation result, or cis/trans phase determination for NM_001903.5:c.*17C>T. BP2 therefore cannot be assessed and is not applied.

Rule

Generic ACMG/AMP BP2: consider only with documented cis/trans observation of the variant with a pathogenic or benign allele in the appropriate inheritance context; no such observation is available.

Evidence considered

• The available evidence contains no documented pathogenic or benign partner variant, affected proband, pedigree, segregation result, or cis/trans phase for NM_001903.5:c.*17C>T.
• The reviewed CTNNA1 clinical guideline is not a report of this variant and supplies no allelic observation usable for BP2.

Still missing

• No report identifies a pathogenic or benign allele paired with c.*17C>T.
• No cis/trans phase determination or affected-proband segregation data are available.

Sources

Reasoning

No reliable co-occurrence evidence is available showing this variant in trans or in the same affected individual with an established pathogenic variant that explains the phenotype. The available materials contain no variant-specific phase, co-occurrence, or likelihood-ratio measurement for BP5, so the criterion cannot be assessed.

Rule

Assess BP5 only from documented variant-specific co-occurrence with another pathogenic variant that accounts for the phenotype, using the governing criterion's own rule and operator when specified; no such evidence was available.

Evidence considered

• The reviewed case materials provide no affected-individual co-occurrence observation, phase information, or validated pathogenic comparator for NM_001903.5:c.*17C>T.
• No BP5 likelihood-ratio-style metric or criterion-specific numeric threshold was supplied by an applicable VCEP or case evidence source; no numeric comparison can therefore be performed.

Still missing

• Variant-specific co-occurrence and phase data are unavailable.
• No governing BP5 likelihood-ratio value or comparison is available for this case.

Reasoning

BP6 requires an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The available ClinVar record is not an exact match: it describes c.2472C>T rather than c.*17C>T, has zero expert-panel submissions, and contains only ordinary single-submitter laboratory assertions. Those assertions cannot trigger BP6.

Rule

Apply BP6 only when an exact-variant ClinVar expert-panel assertion classifies the variant as Benign or Likely benign; non-expert or non-exact records do not qualify.

Evidence considered

• ClinVar variation 1109167 is explicitly flagged as a no-exact-match record because it describes NM_001903.5(CTNNA1):c.2472C>T (p.Asn824=), not NM_001903.5:c.*17C>T.
• The ClinVar audit reports zero expert-panel submissions and only criteria-provided single-submitter laboratory records classified as Likely benign or Benign.
• Under the requested rule, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions cannot trigger BP6.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign classification is available.

Sources

Reasoning

BP7 is in scope because the variant is annotated as synonymous. However, the calibrated SpliceAI result is unavailable: SpliceAI returned no score and max delta is null. This missing result cannot be treated as evidence of absent splice impact, and the available Pangolin values are not calibrated for this assessment; therefore BP7 cannot be assessed.

Evidence considered

• SpliceAI returned no score for NM_001903.5:c.*17C>T; max delta is unavailable, so the missing result must not be interpreted as evidence of no splice impact.
• Pangolin scores are present but are not calibrated for PP3/BP4/BP7 in this assessment and were not used.

Still missing

• A calibrated splice-impact prediction, preferably a valid SpliceAI max delta score, is needed to determine whether BP7 can be applied.

Sources