Classification rationale

BS1BP1 Likely Benign

APC c.3479C>A missense · exon 17

BS1 (Strong): population allele frequency 0.048% in gnomAD v4.1 exceeds the >=0.001% benign threshold by ~48-fold in both gnomAD releases. BP1 (Supporting): missense change outside the VCEP's excepted beta-catenin repeat (codons 1021-1035) is consistent with benign supporting evidence. Overall: Likely Benign — BS1 (Strong) + BP1 (Supporting), no pathogenic criteria met (APC VCEP v2.1).

BS1 + BP1 → Likely Benign

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): highest observed population allele frequency 0.048% exceeds the >=0.001% BS1 threshold in both gnomAD releases.

APC VCEP BS1: gnomAD popmax filtering AF >=0.001% (0.00001).gnomAD v4.1: total AF 0.02695% (435/1,613,950 alleles); highest observed population AF 0.04802% (30/62,480); grpmax FAF 0.031285%; zero homozygotes.gnomAD v2.1: total AF 0.01134% (32/282,180 alleles); highest observed population AF 0.02329% (30/128,808) in non-Finnish European individuals; grpmax FAF 0.016883%; zero homozygotes.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

✓

BP1 supporting review Benign

Met (Supporting): p.Thr1160Lys falls outside the excepted beta-catenin repeat (codons 1021-1035), where missense is generally benign in APC.

APC VCEP Specifications v2.1, BP1 rule text: '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).' Default strength Benign Supporting.Variant codon position 1160 falls outside the excepted codon range 1021-1035, per protein annotation NP_001120982.1:p.(Thr1160Lys).

cspec ↗

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

Pathogenic

PS1 Not met: no established Pathogenic or Likely Pathogenic APC missense produces p.Thr1160Lys; only codons 1026 and 1028 qualify.

PS2 Not assessed: no de novo observation with both parents tested was available for this variant.

PS3 Not assessed: no functional assay data (protein or RNA) for this specific variant was available.

PS4 Not assessed: insufficient individual-level phenotype detail was available to assign phenotype points.

PM2 Not met: gnomAD v4.1 allele frequency 0.02695% (435 alleles) far exceeds the <=0.0003% PM2 threshold.

PM5 Not met: no established Pathogenic or Likely Pathogenic missense variant at codon 1160; only codons 1026 and 1028 qualify.

PM6 Not assessed: no observation of this variant as de novo with parental relationships unconfirmed was available.

PP1 Not assessed: no pedigree or affected-relative data were available to establish co-segregation.

PP3 Not met: SpliceAI predicts no splice impact (all four delta scores 0.00, below the 0.2 threshold).

Benign

BA1 Not met: highest observed population allele frequency 0.048% is below the >=0.1% BA1 threshold.

BS2 Not met: zero homozygotes and no healthy-individual observations meeting the VCEP requirements (>=10 points) were available.

BS3 Not assessed: no protein functional assay data for this variant were available; the RNA-assay arm does not apply to missense changes.

BS4 Not assessed: no affected relative tested negative for this variant, and no non-segregation phenotype data were available.

BP2 Not assessed: no qualifying co-occurring pathogenic APC variant or phase information was available.

BP5 Not assessed: no evidence of an alternate molecular diagnosis in a p.Thr1160Lys carrier was available.

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= 0.000269525; MAF= 0.02695%, 435/1613950 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000480154; MAF= 0.04802%, 30/62480 alleles, homozygotes = 0); grpmax FAF= 0.00031285.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000113403; MAF= 0.01134%, 32/282180 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000232905; MAF= 0.02329%, 30/128808 alleles, homozygotes = 0); grpmax FAF= 0.00016883.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001086130118388183, 2/18414 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.027% · 435 / 1,613,950
0 hom · FAF 0.031%

Remaining individuals 30 / 62,480	0.048%
European (non-Finnish) 402 / 1,180,000	0.034%
African/African American 3 / 74,918	0.004%

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

gnomAD v2.1

0.011% · 32 / 282,180
0 hom · FAF 0.017%

European (non-Finnish) 30 / 128,808	0.023%
African/African American 2 / 24,810	0.0081%

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

gnomAD Canada 🇨🇦

0.011% · 2 / 18,414
0 hom · FAF 0.003%

European (non-Finnish)

2 / 11,734

0.017%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Uncertain significance (7 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 41503)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.523. BayesDel score = 0.307455.

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; COSV57403576, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

18199528 ↗ Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

22703879 ↗ Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. CLINVAR