Variant classification summary

NM_001127511.3:c.1636C>T

APC · NP_001120983.2:p.(Arg546Ter) · NM_001127511.3

GRCh37: chr5:112164616 C>T · GRCh38: chr5:112828919 C>T

Gene: APC Transcript: NM_001127511.3

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

APC

Transcript

NM_001127511.3

Protein

NP_001120983.2:p.(Arg546Ter)

gnomAD AF

6.196823508269661e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127511.3:c.1636C>T (p.Arg546Ter) is a nonsense variant in APC, a gene where loss of function is the established mechanism for familial adenomatous polyposis.

2

This variant introduces a premature termination codon at position 546, upstream of the last exon-exon junction, predicting nonsense-mediated decay and complete loss of the C-terminal 2297 amino acids including all β-catenin binding and regulatory domains.

3

The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,730 alleles; AF=6.2×10⁻⁷), meeting PM2_Supporting under APC VCEP v2.1.0.

4

ClinVar classifies this variant as Pathogenic based on submissions from multiple clinical laboratories, though individual case-level phenotype annotation is not publicly available for PS4 assessment.

5

SpliceAI predicts no cryptic splice impact (max delta=0.01), consistent with this being a straightforward null variant rather than a splicing defect.

Final determination: Rule20 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.1636C>T is a nonsense variant (p.Arg546Ter) in APC, a gene where loss of function is the established disease mechanism for familial adenomatous polyposis. The premature termination codon at position 546 lies upstream of the last exon-exon junction (c.1904/1905) by 269 nucleotides, well beyond the 50-55 nucleotide NMD boundary, predicting nonsense-mediated decay. Under the ClinGen InSiGHT APC VCEP v2.1.0, null variants in APC qualify for PVS1.	gnomad_v4 pvs1_generic_framework cspec
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic variant. NM_001127511.3:c.1636C>T creates a premature stop codon (p.Arg546Ter), a nonsense change. There is no previously classified pathogenic nonsense variant at codon 546 identified in ClinVar or the APC VCEP records to satisfy PS1. The APC VCEP specifies PS1 applies only to missense and splice variants.	cspec pm5_candidates
PS2	Not assessed	No de novo occurrence with confirmed paternity and maternity has been identified for NM_001127511.3:c.1636C>T in the available literature, ClinVar submissions, or exploratory search results.
PS3	Not assessed	No well-established functional study directly evaluating NM_001127511.3:c.1636C>T was identified. The APC VCEP PS3 rules require RNA assay evidence showing a premature stop codon or exon skipping, which has not been reported for this specific variant. The residue (Arg546) lies outside the β-catenin binding domain (codons 959-2129), so protein-level functional assays for β-catenin interaction are not applicable.	cspec
PS4	Not assessed	ClinVar lists NM_001127511.3:c.1636C>T as Pathogenic with clinical laboratory submissions, but disaggregated case counts with phenotype points per the APC VCEP Table 1 are not available from the current evidence. The single individual in gnomAD v4.1 lacks phenotype annotation. Phenotype point scoring could not be completed.	clinvar cspec
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion. The closest criterion, PP5 (reputable source reports variant as pathogenic), is designated Not Applicable for this VCEP per ClinGen SVI recommendations.	cspec
PM1	N/A	PM1 is designated Not Applicable for APC by the ClinGen InSiGHT VCEP v2.1.0 based on current knowledge that no well-defined mutational hotspot or critical functional domain without benign variation has been established.	cspec
PM2	Met	NM_001127511.3:c.1636C>T is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,730 alleles; AF=6.2e-7). Under the APC VCEP v2.1.0, PM2_Supporting is met when the allele count is ≤1 and the allele frequency is <0.001% (0.00001). The observed AF of 0.000062% is below this threshold.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	PM5 requires a different missense change at the same amino acid residue as a known pathogenic missense variant. NM_001127511.3:c.1636C>T is a nonsense variant (p.Arg546Ter), not a missense change. The APC VCEP PM5 rule specifically addresses missense variants and Grantham distance comparisons, which are not applicable to stop-gain variants.	cspec pm5_candidates
PM6	Not assessed	No assumed de novo observation (without confirmation of paternity and maternity) has been identified for NM_001127511.3:c.1636C>T in the available literature, ClinVar submissions, or exploratory search results.
PP1	Not assessed	No co-segregation data has been identified for NM_001127511.3:c.1636C>T in the available literature or databases. The APC VCEP requires ≥3 meioses in ≥1 family for PP1_Supporting, which cannot be evaluated without family studies.
PP2	N/A	PP2 is designated Not Applicable for APC by the ClinGen InSiGHT VCEP v2.1.0 because missense variants are not a frequent mechanism of disease in APC; truncating variants are the predominant pathogenic mechanism.	cspec
PP3	Not met	Under the APC VCEP v2.1.0, PP3 is applicable only to missense variants (via in silico splicing predictors to reveal possible splice effects) and non-canonical splicing variants. NM_001127511.3:c.1636C>T is a nonsense variant. SpliceAI predicts no significant splice impact (max delta score = 0.01). BayesDel score of 0.66 is not actionable under the VCEP PP3 rule, which prohibits use of conservation/evolutionary prediction models for missense variants and is silent on nonsense variants.	spliceai bayesdel cspec
PP4	N/A	PP4 is designated Not Applicable for APC by the ClinGen InSiGHT VCEP v2.1.0. The VCEP specifies that the patient's phenotype and family history are already captured by the specifications of PS4 and PS5, so PP4 is not independently used.	cspec
PP5	N/A	PP5 is designated Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee (Biesecker et al. 2018). Reputable source reporting alone is insufficient without independent evaluation of the underlying evidence.	cspec
BA1	Not met	Under the APC VCEP v2.1.0, BA1 requires a gnomAD Popmax Filtering AF ≥0.1% (0.001). NM_001127511.3:c.1636C>T has a maximum population AF of 8.48e-7 (0.00008%) in European non-Finnish, far below the BA1 threshold. The variant is effectively absent from population databases.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Under the APC VCEP v2.1.0, BS1 requires a gnomAD Popmax Filtering AF ≥0.001% (0.00001). NM_001127511.3:c.1636C>T has a maximum population AF of 8.48e-7 (0.00008%) in European non-Finnish, which is below the BS1 threshold of 0.001%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No observation of NM_001127511.3:c.1636C>T in healthy individuals aged ≥50 years with documented absence of polyposis has been identified. The single allele in gnomAD v4.1 (NFE female) lacks phenotype annotation and does not meet the VCEP definition of a healthy individual (age ≥50, <5 adenomatous polyps, absence of Table 1 features).	gnomad_v4 cspec
BS3	Not assessed	BS3 under the APC VCEP requires RNA assay evidence showing no mRNA aberration or protein assay showing retention of wild-type function. NM_001127511.3:c.1636C>T is a nonsense variant predicted to undergo NMD, so BS3 would require experimental demonstration that the variant does NOT cause loss of function, which is biologically unlikely for a premature termination codon. No such evidence has been identified.	cspec
BS4	Not assessed	No evidence for lack of segregation of NM_001127511.3:c.1636C>T with FAP in affected family members has been identified. The APC VCEP requires affected members without the variant to score phenotype points per Table 1.
BP1	N/A	BP1 is applicable to missense variants in a gene where primarily truncating variants cause disease. NM_001127511.3:c.1636C>T is itself a truncating (nonsense) variant, not a missense variant. BP1 is not applicable to null variants that represent the primary disease mechanism.	cspec
BP2	Not assessed	No observation of NM_001127511.3:c.1636C>T in trans with a (likely) pathogenic APC variant has been reported. In a dominant tumor-suppressor disorder with severe phenotype, biallelic pathogenic APC variants would likely be lethal or result in an extremely severe phenotype, but formal documentation is absent.
BP3	N/A	Skipped per instructions: BP3 is not applicable for in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP4	N/A	Under the APC VCEP v2.1.0, BP4 is not applicable for missense variants and is intended for synonymous or intronic variants. NM_001127511.3:c.1636C>T is a nonsense variant in the coding region, which falls outside the scope of BP4.	cspec
BP5	Not assessed	No alternate genetic basis for the colorectal polyposis phenotype (e.g., pathogenic variants in MUTYH, NTHL1, MSH3, POLD1, POLE) has been documented in individuals carrying NM_001127511.3:c.1636C>T. BP5 requires identification of a (likely) pathogenic variant in another adenomatous polyposis gene.
BP6	N/A	BP6 is designated Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Reputable source reporting alone is insufficient without independent evaluation of the underlying evidence.	cspec
BP7	N/A	BP7 under the APC VCEP applies only to synonymous (silent) or intronic variants at or beyond +7/-21 positions where multiple splicing prediction algorithms predict no splice impact. NM_001127511.3:c.1636C>T is a nonsense (stop-gain) variant in the coding region, not a synonymous or intronic variant.	cspec

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