Variant classification summary

NM_001127510.3:c.3205A>G

APC · NP_001120982.1:p.(Arg1069Gly) · NM_001127510.3

GRCh37: chr5:112174496 A>G · GRCh38: chr5:112838799 A>G

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Arg1069Gly)

gnomAD AF

1.4249780057742587e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 strong is met because gnomAD v2.1 Popmax AF 1.127e-05 exceeds the APC VCEP threshold of 0.00001.

2

Likely Benign: BP1 supporting is met because p.Arg1069Gly at codon 1069 lies outside the APC VCEP exception spanning codons 1021-1035.

Final determination: APC InSiGHT VCEP Version 2.1 Rule26 is satisfied by one Benign.Strong criterion (BS1) together with the adjudicated benign evidence set including BP1 supporting, yielding Likely Benign.

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.3205A>G is a missense substitution producing p.(Arg1069Gly), not a null variant covered by the APC PVS1 decision tree.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1	Not met	Not met: no previously established pathogenic or likely pathogenic APC variant produces the same p.Arg1069Gly amino-acid change.	cspec PMID:34545850
PS2	Not assessed	Not assessed: two reported patients lack documented parental testing and a qualifying APC VCEP de novo score.	cspec PMID:34545850
PS3	Not assessed	Not assessed: no validated RNA or protein assay demonstrates increased beta-catenin transcription or decreased beta-catenin binding for APC p.Arg1069Gly.	cspec PMID:34545850
PS4	Not met	Not met: documented qualifying APC phenotype points are 0, below the VCEP's lowest PS4 band of 1-1.5 phenotype point.	cspec PMID:34545850
PM1	N/A	Not applicable: the APC VCEP explicitly designates PM1 as not applicable, and no APC domain-table interval is supplied.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: gnomAD v4.1 AF 1.42498e-05 with AC 23 exceeds the APC VCEP PM2 threshold of 0.000003 for AC greater than one.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP designates PM3 as not applicable for this autosomal-dominant disorder.	cspec
PM4	N/A	Not applicable: p.(Arg1069Gly) is a missense substitution with no in-frame deletion, insertion, or protein-length change for PM4.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not met	Not met: the residue-1069 search found 0 same-residue pathogenic or likely pathogenic comparator variants among 13 candidates.	cspec pm5_candidates
PM6	Not assessed	Not assessed: the two reported patients have no documented de novo status, parental testing, or phenotype-based APC score.	cspec PMID:34545850
PP1	Not assessed	Not assessed: no pedigree or informative meiosis count is reported for the two patients with the variant.	cspec PMID:34545850
PP2	N/A	Not applicable: the APC VCEP explicitly excludes PP2 because missense variants are not a frequent disease mechanism in APC.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: missense REVEL 0.523 is below the PP3 Supporting threshold of 0.644 from the ClinGen SVI calibration.	cspec revel
PP4	N/A	Not applicable: the APC VCEP marks PP4 unavailable because phenotype specificity is handled through its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: the APC VCEP prohibits PP5, and no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists.	cspec clinvar
BA1	Not met	Not met: gnomAD Popmax AF is 1.127e-05 at most, below the APC VCEP BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met: gnomAD v2.1 Popmax AF 1.127e-05 exceeds the APC VCEP BS1 threshold of 0.00001, despite a lower v4.1 estimate.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 0 homozygotes, but no VCEP-defined healthy-individual age and phenotype points are available.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated assay shows wild-type-comparable beta-catenin transcription activity or benign RNA behavior for APC p.Arg1069Gly.	cspec PMID:34545850
BS4	Not assessed	Not assessed: no affected non-carrier or phenotype-point evidence is documented to meet the APC VCEP BS4 thresholds.	cspec PMID:34545850
BP1	Met	Met, supporting: p.Arg1069Gly is at codon 1069, outside the APC BP1 exception spanning codons 1021-1035.	cspec
BP2	Not assessed	Not assessed: two reported patients lack documented trans phase or a second pathogenic APC variant, while the VCEP requires trans observation or three unknown-phase occurrences.	cspec PMID:34545850
BP3	N/A	Not applicable: p.(Arg1069Gly) is a missense substitution, not an in-frame indel in a repetitive region required for BP3.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the APC VCEP excludes BP4 for missense variants, so no predictor score is evaluated for this criterion.	cspec
BP5	Not met	Not met: no qualifying alternate-gene Pathogenic or Likely pathogenic finding is documented for a colorectal polyposis phenotype.	cspec PMID:34545850
BP6	N/A	Not applicable: the APC VCEP prohibits BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign assertion exists.	cspec clinvar
BP7	N/A	Not applicable: BP7 is restricted to synonymous or qualifying intronic variants, whereas this variant is missense.	cspec

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