Variant classification summary

NM_001127510.3:c.221-29G>C

APC · NP_001120982.1:p.? · NM_001127510.3

GRCh37: chr5:112102857 G>C · GRCh38: chr5:112767160 G>C

Gene: APC Transcript: NM_001127510.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 strong BP4 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.?

gnomAD AF

0.000782202303392039 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 stand-alone benign: non-cancer gnomAD v2.1.1 exome popmax filtering AF 0.4767% is ~4.8-fold above the APC VCEP's 0.1% stand-alone benign ceiling.

2

BS1 strong: the same popmax filtering AF clears the VCEP's 0.001% strong-benign ceiling, but is subsumed by BA1 and not added to the tally.

3

BS2 strong: 3 homozygotes in gnomAD v2.1 non-cancer exomes (9 in v4.1) exceed the VCEP's >= 2 homozygote requirement for this near-fully-penetrant dominant disorder.

4

BP4 supporting: SpliceAI max delta 0.02 and Pangolin near zero predict no impact for this intronic variant, below the 0.1 benign threshold.

5

BP7 supporting: at -29, beyond the +7/-21 boundary, with multiple algorithms predicting no splice-consensus impact and no new splice site.

Final determination: APC InSiGHT VCEP v2.1 Rule26 (Benign.Stand Alone, ==1) applies a single BA1 criterion for a Benign classification, and BA1 is met, so the variant is classified as Benign; BS1 and BS2 (strong) provide concordant but non-additive support.

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.221-29G>C is intronic and outside the APC PVS1 decision-tree variant lists, with SpliceAI max delta 0.02 predicting no splice loss of function.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 vcep_apc_specifications_supplementary_material_v2 pvs1_gene_context pvs1_variant_assessment spliceai PMID:25741868 PMID:21368914 PMID:25645574
PS1	Not met	Not met: no previously established pathogenic variant shares this nucleotide, and SpliceAI max delta 0.02 is far below splice-supportive thresholds.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar spliceai gnomad_v2
PS2	Not assessed	Not assessed: no proband-level parental testing or maternity/paternity confirmation exists to compute an APC de novo score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PS3	Not assessed	Not assessed: no RNA, minigene, or protein assay result exists for c.221-29G>C, and the APC VCEP requires RNA assay data showing a premature stop or exon 13/14 skipping.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar PMID:25741868
PS4	Not assessed	Not assessed: no affected carrier with any Table 1 phenotype feature is reported, so the VCEP >=1 phenotype point PS4 minimum cannot be scored.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar gnomad_v2 gnomad_v4 PMID:20301519 PMID:21368914
PM1	N/A	Not applicable: the APC VCEP designates PM1 not applicable, finding no pathogenic germline missense hotspot and no approved critical domain list.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: non-cancer exome allele frequency 0.108% (252 of 233,222 alleles) far exceeds the VCEP PM2 ceiling of 0.0003% for alleles counted more than once.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC InSiGHT VCEP v2.1 designates PM3 as not used because FAP is an autosomal dominant disorder.	cspec
PM4	N/A	Not applicable: the APC VCEP does not use PM4, and c.221-29G>C is an intronic substitution with no protein length change (p.?).	cspec vcep_apc_specifications_supplementary_material_v2 pvs1_variant_assessment
PM5	N/A	Not applicable: the APC VCEP bars PM5 when the mechanism is a splicing defect, and c.221-29G>C is intronic with no amino-acid change.	cspec vcep_apc_specifications_supplementary_material_v2 pm5_candidates
PM6	Not assessed	Not assessed: no assumed-de-novo proband observation or parental testing data exists to compute an APC de novo score.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PP1	Not assessed	Not assessed: no pedigrees, affected relatives, or meiosis counts are reported to meet the >=3-meiosis APC PP1 threshold.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PP2	N/A	Not applicable: the APC VCEP designates PP2 not applicable because missense variants are not a frequent APC mutation mechanism.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: SpliceAI max delta 0.02 and Pangolin near zero, both below the 0.2 supporting threshold for a deleterious splice effect.	cspec vcep_apc_specifications_supplementary_material_v2 spliceai
PP4	N/A	Not applicable: the APC VCEP states PP4 is already captured by PS4 and cannot be used as independent evidence.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	Not met	Not met: ClinVar 217948 has zero expert-panel submissions and only 2-star laboratory assertions, so the expert-panel requirement for PP5 is not satisfied.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BA1	Met	Met: non-cancer gnomAD v2.1 exome popmax filtering AF 0.477% exceeds the VCEP BA1 threshold of 0.1%, giving stand-alone benign evidence.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Met: the same non-cancer gnomAD v2.1 exome popmax filtering AF of 0.477% exceeds the VCEP BS1 threshold of 0.001%, but it is subsumed by BA1.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Met	Met: 3 homozygotes in gnomAD v2.1 non-cancer exomes exceed the VCEP BS2 requirement of at least 2 homozygous observations for this near-fully-penetrant dominant disorder.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no RNA or beta-catenin reporter assay exists for c.221-29G>C, so the APC VCEP BS3 requirement for an assay showing no mRNA aberration is unmet.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar PMID:25741868
BS4	Not assessed	Not assessed: no affected noncarrier with an APC phenotype score is reported to meet the BS4 threshold.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
BP1	N/A	Not applicable: BP1 is restricted to missense variants, and c.221-29G>C is intronic with no amino-acid change.	cspec vcep_apc_specifications_supplementary_material_v2 spliceai
BP2	Not assessed	Not assessed: no source reports c.221-29G>C in trans with a pathogenic APC variant, and no phase data exist to satisfy the VCEP BP2 rule.	cspec clinvar
BP3	N/A	Not applicable: the APC VCEP does not use BP3, and c.221-29G>C is an intronic substitution rather than an in-frame indel in an APC repeat region.	cspec vcep_apc_specifications_supplementary_material_v2 pvs1_variant_assessment
BP4	Met	Met at supporting: intronic c.221-29 variant with SpliceAI max delta 0.02 and Pangolin near zero, both below the 0.1 BP4 threshold.	cspec vcep_apc_specifications_supplementary_material_v2 spliceai
BP5	Not assessed	Not assessed: no colorectal polyposis phenotype and no variant in another polyposis gene is documented, so the VCEP BP5 condition cannot be evaluated.	cspec vcep_apc_specifications_supplementary_material_v2
BP6	Not met	Not met: the ClinVar Likely benign label rests on ordinary laboratory submissions with zero expert-panel assertions, which cannot trigger BP6.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BP7	Met	Met at supporting: intronic at -29 (beyond the -21 boundary) with SpliceAI max delta 0.02 and Pangolin near zero, showing no splice-site impact.	cspec vcep_apc_specifications_supplementary_material_v2 spliceai

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