Variant classification summary

NM_001127510.3:c.4413A>G

APC · NP_001120982.1:p.(Ala1471=) · NM_001127510.3

GRCh37: chr5:112175704 A>G · GRCh38: chr5:112840007 A>G

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Ala1471=)

gnomAD AF

1.2390161220777805e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1.1 non-cancer exomes, with AF 0 and allele count 0.

2

BP4 supporting: SpliceAI maximum delta 0.001 and Pangolin predictions indicate no significant splice impact.

3

BP7 supporting: the synonymous variant has concordant near-zero splice predictions from multiple algorithms.

Final determination: APC VCEP Version 2.1 Rule19 is satisfied by at least two Benign.Supporting criteria, and the met PM2, BP4, and BP7 criteria therefore produce a Likely Benign classification.

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.4413A>G is synonymous, p.(Ala1471=), and SpliceAI max delta 0.001 does not indicate a splice consequence.	cspec spliceai
PS1	N/A	Not applicable: c.4413A>G is synonymous, p.(Ala1471=), whereas the APC PS1 rule is limited to missense or splice variants.	cspec
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, confirmed maternity or paternity, or de novo observation is documented for c.4413A>G.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
PS3	Not assessed	Not assessed: no variant-specific RNA or protein assay result was identified to meet the APC VCEP PS3 requirements.	cspec PMID:25741868
PS4	Not assessed	Not assessed: no exact-variant phenotype points, case-control enrichment estimate, odds ratio, relative risk, or confidence interval is available for the APC PS4 rules.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
PM1	N/A	Not applicable: the APC VCEP explicitly marks PM1 as not applicable, and no APC domain-table entry is supplied for residue 1471.	cspec
PM2	Met	Met at supporting: gnomAD v2.1.1 non-cancer exomes show AF 0 with allele count 0, below the APC PM2 threshold of 0.00001.	cspec gnomad_v2
PM3	N/A	Not applicable: the APC VCEP excludes PM3 because familial adenomatous polyposis is autosomal dominant.	cspec
PM4	N/A	Not applicable: APC VCEP Version 2.1 does not use PM4, and p.(Ala1471=) causes no protein-length change.	cspec
PM5	N/A	Not applicable: p.(Ala1471=) is synonymous, while the APC PM5 rule requires a different missense variant at the same amino-acid residue.	cspec
PM6	Not assessed	Not assessed: no assumed de novo observation, proband phenotype, parental testing, or de novo score is documented for c.4413A>G.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
PP1	Not assessed	Not assessed: zero affected relatives, phenotype-positive carriers, pedigrees, or informative meioses are documented for c.4413A>G.	cspec vcep_apc_specifications_supplementary_material_v2
PP2	N/A	Not applicable: the APC VCEP explicitly marks PP2 as not applicable, and c.4413A>G is synonymous rather than missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.001 is below the 0.2 PP3 supporting threshold for a deleterious splice effect.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP marks PP4 not applicable because phenotype specificity is captured by its PS4 phenotype-point framework.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: the APC VCEP prohibits PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1.1 non-cancer exomes, below the APC BA1 threshold of 0.001.	cspec gnomad_v2
BS1	Not met	Not met: the variant is absent from gnomAD v2.1.1 non-cancer exomes, below the APC BS1 threshold of 0.00001.	cspec gnomad_v2
BS2	Not met	Not met: gnomAD v2.1.1 non-cancer exomes show zero homozygous observations, below the APC BS2 requirement of at least 2.	cspec gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific RNA or protein assay demonstrated normal APC function or splicing under the VCEP BS3 requirements.	cspec PMID:25741868
BS4	Not assessed	Not assessed: no affected non-carrier or qualifying phenotype score is documented to meet the APC BS4 threshold of 0.5 or 1 point.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262
BP1	N/A	Not applicable: BP1 is missense-specific under the APC VCEP, whereas this variant is synonymous at codon 1471.	cspec
BP2	Not assessed	Not assessed: no affected-proband phase data, in-trans pathogenic APC variant, or three qualifying unknown-phase co-occurrences are documented.	cspec
BP3	N/A	Not applicable: APC VCEP Version 2.1 excludes BP3, and this synonymous substitution is not an in-frame repeat-region deletion or insertion.	cspec
BP4	Met	Met at supporting: SpliceAI max delta 0.001 is below the <=0.1 BP4 threshold and predicts no significant splice impact.	cspec spliceai
BP5	Not assessed	Not assessed: no qualifying alternate-gene Pathogenic or Likely pathogenic variant and no documented colorectal polyposis phenotype are available for the APC BP5 rule.	cspec vcep_apc_specifications_supplementary_material_v2
BP6	N/A	Not applicable: the APC VCEP prohibits BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BP7	Met	Met at supporting: the synonymous variant has concordant near-zero splice predictions, including SpliceAI max delta 0.001.	cspec spliceai

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