Variant classification summary

NM_001127510.3:c.4360A>G

APC · NP_001120982.1:p.(Lys1454Glu) · NM_001127510.3

GRCh37: chr5:112175651 A>G · GRCh38: chr5:112839954 A>G

Gene: APC Transcript: NM_001127510.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS3 supporting BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Lys1454Glu)

gnomAD AF

0.0004739418705649263 (v4.1)

ClinVar

Benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 (stand-alone benign) - non-cancer gnomAD v2.1.1 popmax filtering AF 0.6696% clears the 0.1% threshold and alone satisfies the APC VCEP's Benign.Stand Alone rule.

2

Benign: BS1 (strong) - the same VCEP-directed 0.6696% popmax filtering AF exceeds the 0.001% strong-benign ceiling, but is subsumed by BA1.

3

Benign: BS3 (supporting) - a beta-catenin-regulated transcription assay shows K1454E retaining wild-type-comparable activity (PMID:18199528).

4

Benign: BP1 (supporting) - a true missense change at codon 1454, outside the excepted 1021-1035 beta-catenin repeat window, in a gene where truncating variants cause disease.

Final determination: Under the ClinGen InSiGHT APC VCEP v2.1 criteria-combination rules, BA1 (stand-alone benign) alone satisfies the Benign.Stand Alone rule (BA1 == 1), so the variant is classified 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	Not met	Not met: c.4360A>G is a missense substitution (p.Lys1454Glu), not a null variant, and SpliceAI max delta 0.001 excludes a cryptic splice-null allele.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 vcep_apc_specifications_supplementary_material_v2 spliceai PMID:18199528
PS1	Not met	Not met: no established P/LP APC variant shares the p.(Lys1454Glu) amino-acid change; the VCEP recognises only p.(Asn1026Ser) and p.(Ser1028Arg).	cspec clinvar PMID:23970361
PS2	Not assessed	Not assessed: no proband de novo occurrence or parental testing exists, and published germline occurrences of c.4360A>G are inherited, including 2/969 healthy controls (PMID:18199528).	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 gnomad_v4 PMID:18199528 PMID:23970361 PMID:11904335 PMID:18844223
PS3	Not met	Not met: the only functional assay (CRT, PMID:18199528) shows K1454E at about 1.15x wild-type activity, not significantly increased, so no damaging effect is demonstrated.	cspec PMID:18199528 PMID:18844223
PS4	Not met	Not met: reported carriers total 0.5 phenotype points, below the PS4_Supporting minimum of 1 phenotype point (0.5 >= 1? no).	cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2 PMID:23970361 PMID:18199528 PMID:11904335 PMID:21859464 PMID:15604628
PM1	N/A	Not applicable: the APC VCEP specification disables PM1 at every strength, and the VCEP domain table contains no approved critical-domain entries for APC.	cspec
PM2	Not met	Not met: non-cancer gnomAD v2.1.1 allele frequency 0.0583% (138/236,710, AC > 1) far exceeds the PM2 ceiling of 0.0003%.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP v2.1 specification states PM3 is not used because FAP is autosomal dominant, so no recessive in-trans configuration applies.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: the APC VCEP discontinues PM4, and c.4360A>G is a substitution with no protein-length change.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not met	Not met: no different missense at codon 1454 is established Pathogenic/Likely Pathogenic (VCEP lists only p.(Asn1026Ser) and p.(Ser1028Arg)).	cspec pm5_candidates clinvar PMID:11904335 PMID:18844223 PMID:18199528
PM6	Not assessed	Not assessed: no assumed de novo occurrence is documented; the variant is inherited in published reports (PMID:18199528) and present in gnomAD v4.1 at 765 alleles with 9 homozygotes.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 gnomad_v4 PMID:18199528 PMID:23970361 PMID:11904335 PMID:18844223
PP1	Not assessed	Not assessed: no pedigree or meioses are available for c.4360A>G, and the APC VCEP requires at least 3 meioses in one family even for supporting PP1.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23970361 PMID:18199528
PP2	N/A	Not applicable: the APC VCEP specification disables PP2 because missense variants are not a frequent disease mechanism in APC.	cspec
PP3	Not met	Not met: SpliceAI maximum delta 0.001 is below the 0.2 supporting threshold, giving no deleterious splice evidence.	cspec spliceai
PP4	N/A	Not applicable: APC VCEP specifications fold PP4 into PS4 and forbid it as independent evidence, so no separate phenotype points are scored.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	Not met	Not met: zero ClinVar expert-panel submissions for this variant (aggregate Benign from single submitters), so no expert-panel pathogenic assertion triggers PP5.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar PMID:15604628
BA1	Met	Met: the VCEP-directed non-cancer gnomAD v2.1.1 popmax filtering AF is 0.6696%, far above the BA1 threshold of 0.1%.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met: the VCEP-directed non-cancer gnomAD v2.1.1 popmax filtering AF of 0.6696% exceeds the BS1 threshold of 0.001%, though BA1 stand-alone supersedes it.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: the VCEP-directed non-cancer gnomAD v2.1.1 dataset shows zero homozygotes and healthy-control carriers total about 1 point, below the >= 3 needed.	cspec gnomad_v2 gnomad_v4 PMID:18199528 PMID:11904335 PMID:23970361
BS3	Met	Met at Supporting: CRT assay (PMID:18199528) shows K1454E retains beta-catenin-regulated transcription comparable to wild type (about 1.15x, not significant) in a codon-1454 variant.	cspec PMID:18199528 clinvar oncokb
BS4	Not assessed	Not assessed: no genotyped family members exist, so no affected non-carrier can be scored against the >= 1 Table 1 phenotype-point threshold for BS4.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:23970361 PMID:18199528 PMID:11904335
BP1	Met	Met at supporting: missense at codon 1454 lies outside the APC VCEP's excepted 1021-1035 beta-catenin repeat window in a primarily truncating-mechanism gene.	cspec pvs1_gene_context spliceai
BP2	Not met	Not met: no report shows c.4360A>G in trans with a pathogenic APC variant, nor three unknown-phase occurrences with different pathogenic APC variants.	cspec clinvar gnomad_v2 gnomad_v4 PMID:18199528 PMID:11904335 PMID:23970361 PMID:18844223 PMID:22995991
BP3	N/A	Not applicable: the APC VCEP discontinues BP3, and c.4360A>G is a missense substitution, not an in-frame indel in a repeat region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: the APC VCEP excludes BP4 for missense variants, and this variant is the missense change p.(Lys1454Glu).	cspec
BP5	Not met	Not met: no (likely) pathogenic variant in another adenomatous polyposis gene (POLD1/POLE/MUTYH/NTHL1/MSH3/MMR) is reported for this case.	cspec vcep_apc_specifications_supplementary_material_v2 PMID:11904335
BP6	Not met	Not met: no ClinVar expert-panel Benign/Likely benign assertion exists for this variant (zero expert-panel submissions; aggregate Benign from single submitters).	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BP7	N/A	Not applicable: the variant is the missense change p.(Lys1454Glu), whereas BP7 is restricted to synonymous or qualifying intronic variants.	cspec

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