APC is a tumor suppressor gene whose protein acts as a key brake on the Wnt signaling pathway by helping mark the growth-promoting protein beta-catenin for destruction; it also participates in cell migration, adhesion, and apoptosis. Inherited mutations in APC cause familial adenomatous polyposis (FAP), an autosomal dominant condition characterized by numerous colorectal polyps and a very high risk of colorectal cancer, with related forms including attenuated FAP and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Somatic APC mutations are found in roughly 50-80% of sporadic colorectal cancers, where they act as early tumor-initiating events, and are also observed in some breast, stomach, and prostate cancers. Loss of APC function leaves Wnt signaling abnormally active, driving uncontrolled cell growth, which makes APC a central tumor suppressor in colorectal cancer.
This variant
This APC missense variant affects a tumor-suppressor gene whose loss of function abnormally activates Wnt signaling and contributes to familial adenomatous polyposis and colorectal cancer risk.
Transcript
NM_001127510.3
HGVS · transcript:coding
NM_001127510.3:c.3205A>G
GRCh38
chr5:112838799 A>G
GRCh37
chr5:112174496 A>G
Likely Benign: BS1 (strong) plus BP1 (supporting) satisfy APC InSiGHT VCEP Version 2.1 Rule26.
Classification rationale
BS1BP1Likely Benign
APC c.3205A>Gmissense · exon 17
Likely Benign: BS1 strong is met because gnomAD v2.1 Popmax AF 1.127e-05 exceeds the APC VCEP threshold of 0.00001. Likely Benign: BP1 supporting is met because p.Arg1069Gly at codon 1069 lies outside the APC VCEP exception spanning codons 1021-1035.
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
APCNM_001127510.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in APC—click a row to locate it on the plot · use the link column to open its page
Protein
Location
Classification
Link
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
✓
BS1strongreviewBenign
Met: gnomAD v2.1 Popmax AF 1.127e-05 exceeds the APC VCEP BS1 threshold of 0.00001, despite a lower v4.1 estimate.
The APC InSiGHT VCEP specifies BS1 for gnomAD Popmax Filtering AF >= 0.00001 (0.001%).gnomAD v2.1 reports Popmax Filtering AF 1.127e-05, meeting the threshold.gnomAD v4.1 reports Popmax Filtering AF 6.88e-06, below the threshold; this release discrepancy reduces confidence but does not negate the qualifying v2.1 observation.
Met, supporting: p.Arg1069Gly is at codon 1069, outside the APC BP1 exception spanning codons 1021-1035.
The APC VCEP BP1 rule applies to APC missense variants except those in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.The assessed variant is a missense substitution at codon 1069, which is outside the specified exception interval.
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PS1Not met: no previously established pathogenic or likely pathogenic APC variant produces the same p.Arg1069Gly amino-acid change.
PS2Not assessed: two reported patients lack documented parental testing and a qualifying APC VCEP de novo score.
PS3Not assessed: no validated RNA or protein assay demonstrates increased beta-catenin transcription or decreased beta-catenin binding for APC p.Arg1069Gly.
PS4Not met: documented qualifying APC phenotype points are 0, below the VCEP's lowest PS4 band of 1-1.5 phenotype point.
PM2Not met: gnomAD v4.1 AF 1.42498e-05 with AC 23 exceeds the APC VCEP PM2 threshold of 0.000003 for AC greater than one.
PM5Not met: the residue-1069 search found 0 same-residue pathogenic or likely pathogenic comparator variants among 13 candidates.
PM6Not assessed: the two reported patients have no documented de novo status, parental testing, or phenotype-based APC score.
PP1Not assessed: no pedigree or informative meiosis count is reported for the two patients with the variant.
PP3Not met: missense REVEL 0.523 is below the PP3 Supporting threshold of 0.644 from the ClinGen SVI calibration.
Benign
BA1Not met: gnomAD Popmax AF is 1.127e-05 at most, below the APC VCEP BA1 threshold of 0.001.
BS2Not assessed: gnomAD reports 0 homozygotes, but no VCEP-defined healthy-individual age and phenotype points are available.
BS3Not assessed: no validated assay shows wild-type-comparable beta-catenin transcription activity or benign RNA behavior for APC p.Arg1069Gly.
BS4Not assessed: no affected non-carrier or phenotype-point evidence is documented to meet the APC VCEP BS4 thresholds.
BP2Not assessed: two reported patients lack documented trans phase or a second pathogenic APC variant, while the VCEP requires trans observation or three unknown-phase occurrences.
BP5Not met: no qualifying alternate-gene Pathogenic or Likely pathogenic finding is documented for a colorectal polyposis phenotype.
This variant is present in gnomAD v4.1 (AF= 1.42498e-05; MAF= 0.00142%, 23/1614060 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00205e-05; MAF= 0.00800%, 5/62484 alleles, homozygotes = 0); grpmax FAF= 6.88e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.12879e-05; MAF= 0.00213%, 6/281850 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.01316e-05; MAF= 0.00401%, 1/24918 alleles, homozygotes = 0); grpmax FAF= 1.127e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014%
· 23 / 1,614,060
0 hom · FAF 0.00069%
Remaining individuals
5 / 62,484
0.008%
South Asian
2 / 91,080
0.0022%
Admixed American
1 / 60,012
0.0017%
African/African American
1 / 74,958
0.0013%
European (non-Finnish)
14 / 1,180,036
0.0012%
+ 5 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0021%
· 6 / 281,850
0 hom · FAF 0.0011%
African/African American
1 / 24,918
0.004%
European (non-Finnish)
4 / 128,378
0.0031%
Admixed American
1 / 35,402
0.0028%
+ 5 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 142240)
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.
Triaged references · 8 PMIDs not cited in assessment
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
34545850 ↗Genetic Analysis of Archived Tumor Specimens for Hereditary Colorectal Cancer Syndromes in the Cajuns of Louisiana, a US Founder Population.CLINVAR
7306523 ↗Location of structural domains in protein.CLINVAR
15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.CLINVAR
25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.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
26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiCLINVAR
