Variant classification summary

NM_001127511.3:c.793C>T

APC · NP_001120983.2:p.(Arg265Ter) · NM_001127511.3

GRCh37: chr5:112151204 C>T · GRCh38: chr5:112815507 C>T

Gene: APC Transcript: NM_001127511.3

Final call

Likely Pathogenic

PVS1 very strong PS4 moderate PM2 supporting PP5 supporting

Variant details

Gene

APC

Transcript

NM_001127511.3

Protein

NP_001120983.2:p.(Arg265Ter)

gnomAD AF

2.4830654933354522e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127511.3:c.793C>T (p.Arg265Ter) is a nonsense variant in exon 7 of APC, a gene where loss of function is the established disease mechanism for familial adenomatous polyposis.

2

The variant meets PVS1 at Very Strong strength: null variant in a LOF-established gene, expected to trigger nonsense-mediated decay (InSiGHT VCEP v2.1.0 modified decision tree).

3

The variant has been observed in multiple unrelated families with classic FAP: a 3-generation Malaysian Chinese family (PMID:12901799) and 3 affected individuals from 2 Brazilian families (PMID:30897307), meeting PS4 at Moderate strength (estimated 3.5 phenotype points).

4

The variant is absent from gnomAD v2.1.1 and present at extremely low frequency in gnomAD v4.1 (AF=2.48e-6, grpmax FAF=8e-7), meeting PM2 at Supporting strength under APC VCEP population thresholds.

5

Under the APC VCEP v2.1.0 combination rules (Rule 22): one Very Strong criterion (PVS1) + one Moderate criterion (PS4) + one Supporting criterion (PM2) reaches Pathogenic classification. The ClinGen InSiGHT expert panel independently classified this variant as Pathogenic (ClinVar variation 184999).

Final determination: Rule18 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0 v2.1.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Pathogenic.

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	Met	NM_001127511.3:c.793C>T is a nonsense variant producing p.Arg265Ter (p.R265*) in exon 7. APC is a gene where loss of function is the established mechanism of disease (InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP v2.1.0). The premature termination codon at position 265 occurs well upstream of the last exon, and nonsense-mediated decay is expected. Under the APC VCEP modified PVS1 decision tree (Figure 1), this null variant meets PVS1 at Very Strong strength.	cspec pvs1_gene_context pvs1_variant_assessment PMID:12901799 PMID:30897307
PS1	N/A	PS1 applies to missense or splice variants with the same amino acid change as a previously established Pathogenic/Likely Pathogenic variant. This variant is a nonsense change (p.Arg265Ter); PS1 is not applicable to nonsense variants under the APC VCEP framework.	cspec
PS2	Not assessed	No de novo observations have been reported for this variant in the available literature or databases. PS2 requires confirmed de novo occurrence with confirmed maternity and paternity.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been performed for this variant. The APC VCEP PS3 criteria require RNA assays demonstrating a premature stop codon with defined full-length transcript levels, or specific protein assay evidence. OncoKB's 'Likely Loss-of-function' annotation is a computational inference, not experimental functional evidence for germline PS3.	oncokb
PS4	Met	The variant has been observed in multiple unrelated families with classic FAP. PMID:12901799 reports a 3-generation Malaysian Chinese family with multiple affected members segregating the variant with disease (estimated ≥2 phenotype points). PMID:30897307 reports 3 affected individuals from 2 unrelated Brazilian families (families 10 and 21), all with classic FAP and one with osteoma (estimated ≥1.5 phenotype points). Total estimated phenotype points: 3.5, meeting PS4_Moderate threshold (2-3.5 points) under the APC VCEP phenotype point system (Table 1).	clinvar PMID:12901799 PMID:30897307
PS5	N/A	PS5 is not defined within the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP v2.1.0 framework for APC. Not used.	cspec
PM1	N/A	PM1 is designated 'Not Applicable' by the APC VCEP v2.1.0. No mutational hotspot or functional domain criteria are defined within this framework.	cspec
PM2	Met	The variant is absent from gnomAD v2.1.1 (non-cancer dataset, AC=0) and present at extremely low frequency in gnomAD v4.1 (AF=2.48e-6, 4/1,610,912 alleles, grpmax FAF=8e-7). Under the APC VCEP PM2 threshold: AC=0 (≤1) requires AF<0.001% (1e-5); absent from v2.1.1 meets this. Under the alternative threshold for AC>1: AF≤0.0003% (3e-6); the v4.1 AF of 2.48e-6 also meets this. PM2_Supporting is satisfied.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	PM5 is applicable only to missense variants under the APC VCEP. This is a nonsense variant (p.Arg265Ter). The PM5 candidate scan confirmed no eligible same-residue missense comparators.	cspec pm5_candidates
PM6	Not assessed	No assumed or confirmed de novo observations have been reported for this variant. PM6 requires de novo occurrence data (with or without parental confirmation) scored per the APC VCEP Tables 1 and 2.
PP1	Not met	PMID:12901799 reports segregation of the variant with disease in a 3-generation FAP family, representing approximately 2-3 meioses in one family. The minimum threshold for PP1_Supporting under the APC VCEP is 3-4 meioses in at least one family. The available evidence falls below this threshold.	PMID:12901799 PMID:30897307
PP2	N/A	PP2 is designated 'Not Applicable' by the APC VCEP v2.1.0. Missense variants are not a frequent mechanism of disease in APC.	cspec
PP3	N/A	Under the APC VCEP v2.1.0, PP3 is applicable only to missense variants (for in silico splicing predictor evaluation) and non-canonical splicing variants. This is a nonsense variant producing a premature termination codon; the pathogenic mechanism is loss of normal protein function through truncation and NMD. Computational prediction is not relevant to this established null effect. SpliceAI max delta score is 0.19, consistent with no cryptic splice effect.	cspec spliceai
PP4	N/A	PP4 is designated 'Not Applicable' by the APC VCEP v2.1.0. Phenotype specificity is already captured by the PS4 phenotype point system and therefore PP4 is not used.	cspec
PP5	Met	Expert panel ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	Under the APC VCEP, BA1 requires gnomAD Popmax Filtering AF ≥0.1% (0.001). The variant's grpmax FAF in gnomAD v4.1 is 8e-7 (0.00008%), far below the BA1 threshold. The variant is absent from gnomAD v2.1 entirely.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Under the APC VCEP, BS1 requires gnomAD Popmax Filtering AF ≥0.001% (1e-5). The variant's grpmax FAF in gnomAD v4.1 is 8e-7 (0.00008%), which is below the BS1 threshold.	gnomad_v4 cspec
BS2	Not assessed	No documented observations of this variant in healthy adults meeting the APC VCEP criteria (age ≥50 years, <5 adenomatous polyps, no FAP features) have been reported. The 4 alleles in gnomAD v4.1 lack phenotype data and cannot be assumed to represent healthy individuals for BS2.
BS3	Not assessed	No well-established functional studies demonstrating a benign effect have been reported for this variant. The APC VCEP BS3 criteria require RNA assays showing no mRNA aberration in constitutional patient samples, or specific protein assay evidence; none are available.
BS4	Not assessed	No evidence of affected family members lacking the variant has been reported. BS4 requires documentation of affected individuals without the variant meeting specific phenotype point thresholds.
BP1	N/A	BP1 is a criterion for missense variants in genes where primarily truncating variants cause disease. This variant is itself a truncating (nonsense) variant; BP1 is not applicable to nonsense variants.	cspec
BP2	Not assessed	No evidence of this variant occurring in trans with a (likely) pathogenic APC variant or in unknown phase with multiple different (likely) pathogenic APC variants has been reported.
BP4	N/A	Under the APC VCEP v2.1.0, BP4 is not applicable to missense variants and is used only for synonymous (silent) or intronic variants where multiple splicing predictors suggest no impact. This is a nonsense variant.	cspec
BP5	Not assessed	No evidence of an alternate molecular basis for the colorectal polyposis phenotype (e.g., pathogenic variants in POLD1, POLE, MUTYH, NTHL1, or MSH3) has been reported in individuals carrying this variant.
BP6	N/A	BP6 is designated 'Not Applicable for this VCEP' by the ClinGen InSiGHT VCEP v2.1.0. Not used.	cspec
BP7	N/A	BP7 is applicable to synonymous (silent) or intronic variants at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact. This is a nonsense variant (c.793C>T, p.Arg265Ter); BP7 does not apply.	cspec
BP3	N/A	BP3 is not applicable to substitution variants (in-frame deletion/insertion in repetitive region). Variant is a substitution.
PM3	N/A	PM3 is for recessive disorders. FAP/APC is autosomal dominant; PM3 is not applicable.	cspec
PM4	N/A	PM4 is for protein length changes due to in-frame deletions/insertions or stop-loss. This is a substitution (nonsense), not an in-frame change or stop-loss. VCEP also designates PM4 as not used.	cspec

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