Classification rationale

BS1BP1 Likely Benign

APC c.3245C>G missense · exon 17

Likely Benign driver: BS1 (strong) - gnomAD v2.1.1 non-cancer popmax filtering AF 0.0039% exceeds the APC VCEP threshold of 0.001%. Likely Benign: BP1 (supporting) - missense change at residue 1082 sits outside the VCEP-excepted beta-catenin repeat codons 1021-1035. Likely Benign: APC VCEP Rule26 is met by one Benign-Strong criterion, while no pathogenic combination rule is satisfied.

BS1 + BP1 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001127510.3 · variants mapped to exon structure

APC NM_001127510.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

Met (strong): popmax filtering AF 0.0039% in gnomAD v2.1 non-cancer exceeds the VCEP BS1 threshold of 0.001%.

Governing specification: InSiGHT APC VCEP v2.1. BS1 strength rule: 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001).' instructionsToUse: 'General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1)'.gnomAD v2.1.1 non-cancer subset: grpmax filtering AF 3.865e-05 (0.003865%); exome AC 11, AN 236026, exome AF 4.6605035e-05; highest subpopulation European (Finnish) AF 0.00011951238945103975 (0.011950%), above the 0.001% threshold.gnomAD v2.1 all-comers: grpmax filtering AF 3.442e-05 (0.003442%); gnomAD v4.1 all-comers: grpmax filtering AF 7.076e-05 (0.007076%). Both exceed 0.001%.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP1 supporting Benign

Met (supporting): p.Thr1082Ser is a missense change at residue 1082, outside the beta-catenin repeat codons 1021-1035 that the APC VCEP excepts.

ClinGen InSiGHT APC VCEP specification v2.1 (cspec), BP1 Supporting rule: 'BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the beta-catenin binding domain (codon 1021-1035).'The variant under assessment is a missense change at residue 1082 (p.Thr1082Ser), which is outside codons 1021-1035, so the VCEP exception does not remove BP1 applicability.APC is a gene in which primarily truncating (loss-of-function) variants are known to cause familial adenomatous polyposis 1 (MONDO:0021056); this is the mechanism premise of BP1.

cspec ↗

Assessed · not applied · 9 not met · 6 not assessed

Pathogenic

PS1 Not met: no established pathogenic variant carries the same p.Thr1082Ser change; APC's only Likely Pathogenic missense variants are p.Asn1026Ser and p.Ser1028Arg.

PS2 Not assessed: no proband with confirmed parentage or documented de novo occurrence, so no de novo score could be counted against the VCEP >=4/2-3.5/1-1.5 thresholds.

PS3 Not assessed: no RNA or protein functional assay has been reported for APC p.(Thr1082Ser), so the APC VCEP PS3 requirements cannot be evaluated.

PS4 Not met: 0 phenotype points assignable (no polyposis phenotype documented) against the >=1 phenotype point required for PS4_Supporting.

PM2 Not met: non-cancer exome AF 0.00466% (11 alleles) exceeds the VCEP PM2 threshold of 0.0003% for allele count greater than 1.

PM5 Not met: residue 1082 has no pathogenic alternate missense; the APC VCEP restricts PM5 to residues 1026 and 1028.

PM6 Not assessed: no de novo occurrence, even with unconfirmed parentage, is reported, so no VCEP PM6 de novo score (0.5-3.5) can be assigned.

PP1 Not assessed: no pedigree or meiosis data are reported, so co-segregation cannot be counted against the VCEP >=7/5-6/3-4 meiosis thresholds.

PP3 Not met: for APC missense variants PP3 uses splice predictors, and SpliceAI max delta 0.001 is far below the 0.2 supporting cutoff.

Benign

BA1 Not met: highest popmax filtering AF 0.0039% (gnomAD v2.1 non-cancer) versus the VCEP BA1 stand-alone threshold of 0.1%.

BS2 Not met: zero homozygotes across every gnomAD dataset, and the VCEP bars counting gnomAD heterozygous carriers as healthy individuals.

BS3 Not assessed: no protein assay showing retained beta-catenin-regulated transcription has been reported for APC p.(Thr1082Ser), so the APC VCEP BS3 protein-assay branch is unevaluable.

BS4 Not assessed: no genotyped affected relative without the variant is reported, so no phenotype-point deficit can be scored for VCEP BS4.

BP2 Not met: no source reports c.3245C>G in trans with a pathogenic APC variant, and none of the required >=3 unknown-phase co-occurrences exist.

BP5 Not met: no (likely) pathogenic variant in another adenomatous polyposis gene is documented, so the alternate-molecular-basis condition for BP5_Supporting is absent.

N/A · 11 PVS1 · PM1 · PM3 · PM4 · PP2 · PP4 · PP5 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.87714e-05; MAF= 0.00688%, 111/1614042 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000112029; MAF= 0.01120%, 7/62484 alleles, homozygotes = 0); grpmax FAF= 7.076e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.61448e-05; MAF= 0.00461%, 13/281722 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000119436; MAF= 0.01194%, 3/25118 alleles, homozygotes = 0); grpmax FAF= 3.442e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0069% · 111 / 1,614,042
0 hom · FAF 0.0071%

Remaining individuals 7 / 62,484	0.011%
European (non-Finnish) 100 / 1,180,040	0.0085%
European (Finnish) 4 / 64,000	0.0063%

+ 7 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0046% · 13 / 281,722
0 hom · FAF 0.0034%

European (Finnish) 3 / 25,118	0.012%
European (non-Finnish) 10 / 128,316	0.0078%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 181799)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.293. BayesDel score = -0.278933.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. APC, a tumor suppressor involved in WNT signaling, is recurrently altered in colorectal cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57391633, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

25142776 ↗ Comprehensive screening for mutations associated with colorectal cancer in unselected cases reveals penetrant and nonpenetrant mutations. CLINVAR

25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Cl CLINVAR

25559809 ↗ Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (CRC) is achievable for a high proportion of familial CRC by exome sequencing. CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointes CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR

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