Variant classification summary

NM_001127510.3:c.-11G>C

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

GRCh37: chr5:112090577 G>C · GRCh38: chr5:112754880 G>C

Gene: APC Transcript: NM_001127510.3

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(=)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 (supporting) is met because the variant is absent from gnomAD v2.1.1 non-cancer.

2

VUS: BP7 (supporting) is met because SpliceAI and Pangolin predict no meaningful splice impact.

Final determination: Under the APC InSiGHT VCEP Version 2.1 criteria-combination framework, PM2 supporting plus BP7 supporting do not satisfy any classification rule, leaving the variant as a 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.-11G>C is a 5′ UTR synonymous-equivalent change, p.(=), not a specified APC null or canonical splice variant for PVS1.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 pvs1_variant_assessment
PS1	N/A	Not applicable: c.-11G>C is a synonymous 5′-UTR variant with p.(=), not a missense or same-nucleotide splice variant.	cspec vcep_apc_specifications_supplementary_material_v2
PS2	Not assessed	Not assessed: no proband phenotype score, parental testing, or documented de novo observation is available to calculate the APC VCEP PS2 score.	cspec
PS3	Not assessed	Not assessed: no variant-specific RNA or protein assay result is available to satisfy the APC VCEP PS3 requirements.	cspec
PS4	Not assessed	Not assessed: no proband phenotype, phenotype-point total, or case-control enrichment estimate is available for this exact APC variant.	cspec
PM1	N/A	Not applicable: the APC VCEP designates PM1 as not applicable, and this synonymous variant has no translated residue for domain assessment.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1.1 non-cancer, giving AF 0 versus the APC PM2 threshold of <0.001% (0.00001) when AC <=1.	cspec gnomad_v2
PM3	N/A	Not applicable: the APC VCEP specifies PM3 is not used because familial adenomatous polyposis is autosomal dominant.	cspec
PM4	N/A	Not applicable: APC VCEP does not use PM4, and the 5′ UTR change produces p.(=) with no protein length alteration.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	N/A	Not applicable: c.-11G>C is synonymous with p.(=), so no amino-acid residue exists for the APC same-residue missense PM5 rule.	cspec vcep_apc_specifications_supplementary_material_v2 pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo observation or phenotype-based de novo score is documented for APC c.-11G>C.	cspec
PP1	Not assessed	Not assessed: no affected-relative genotypes, family structure, or meiosis count is documented to evaluate APC segregation.	cspec
PP2	N/A	Not applicable: the APC VCEP designates PP2 as not applicable, and c.-11G>C is synonymous rather than missense.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	N/A	Not applicable: the variant is synonymous, whereas PP3 is restricted here to missense or intronic/splice-region variants assessed through the SpliceAI path.	cspec
PP4	N/A	Not applicable: the APC VCEP explicitly excludes PP4 because phenotype specificity is captured by its PS4 phenotype-point framework.	cspec
PP5	N/A	Not applicable: APC excludes PP5, and ClinVar has only a single-laboratory uncertain-significance submission with no expert-panel Pathogenic classification.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1.1 non-cancer, below the APC VCEP BA1 threshold of 0.1% (0.001).	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1.1 non-cancer, below the APC VCEP BS1 threshold of 0.001% (0.00001).	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1.1 non-cancer reports no homozygous observations, versus the APC VCEP threshold of at least 2 homozygotes.	cspec gnomad_v2
BS3	Not assessed	Not assessed: no variant-specific RNA assay with required controls or qualifying protein assay demonstrates preserved APC function.	cspec
BS4	Not assessed	Not assessed: no affected relative lacking APC c.-11G>C or phenotype-point score is documented for non-segregation.	cspec
BP1	N/A	Not applicable: BP1 is a missense criterion, whereas c.-11G>C is synonymous and lies in the 5′ untranslated region with p.(=).	cspec vcep_apc_specifications_supplementary_material_v2
BP2	Not assessed	Not assessed: no qualifying trans observation or at least 3 unknown-phase observations with different pathogenic APC variants is documented.	cspec
BP3	N/A	Not applicable: APC VCEP excludes BP3, and c.-11G>C causes p.(=) without an in-frame protein length change or repeat-region indel.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the variant is synonymous and not an intronic/splice-region variant, so BP4's missense or SpliceAI-path scope is not met.	cspec
BP5	Not assessed	Not assessed: no qualifying alternate pathogenic gene finding and no documented colorectal polyposis phenotype are available for BP5.	cspec
BP6	N/A	Not applicable: APC excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	Met	Met, Supporting: synonymous variant with SpliceAI maximum delta 0.013 and Pangolin scores 0.012/-0.002 supports no splice impact.	cspec spliceai

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