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APC
Final classification
Likely Benign
PM2BP4BP7
APC
c.8511T>C
p.Ser2837=
synonymous · exon 17
Gene context NCBI Gene ↗ OncoKB ↗

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

APC is a tumor suppressor whose loss drives Wnt-pathway activation, familial adenomatous polyposis, and most sporadic colorectal cancers. This synonymous variant leaves the APC protein unchanged and is predicted to have no splicing effect, so it does not indicate elevated colorectal cancer or polyposis risk.

Transcript
NM_001127510.3
HGVS · transcript:coding
NM_001127510.3:c.8511T>C
GRCh38
chr5:112844105 T>C
GRCh37
chr5:112179802 T>C
Basis APC VCEP CSPEC v2.1 applied: PM2, BP4, and BP7 met at supporting strength; Rule 19 satisfied by BP4+BP7, no pathogenic rule met, yielding Likely Benign. ▾
APC VCEP CSPEC v2.1 applied: PM2, BP4, and BP7 met at supporting strength; Rule 19 satisfied by BP4+BP7, no pathogenic rule met, yielding Likely Benign.
Classification rationale
PM2 BP4BP7 Likely Benign
APC c.8511T>C synonymous · exon 17

PM2 (Supporting): absent from gnomAD v2.1, the APC panel's designated population dataset. BP4 (Supporting): SpliceAI max delta 0.00 predicts no splice impact, indicating no effect on gene or gene product. BP7 (Supporting): synonymous change with SpliceAI max delta 0.00 predicts no splice-consensus disruption or new splice site. Three supporting benign criteria (PM2 + BP4 + BP7) satisfy APC VCEP Rule 19's benign combination while no pathogenic rule is met, yielding Likely Benign.

PM2 + BP4 + BP7 → Likely Benign
Gene diagram · NM_001127510.3 · variants mapped to exon structure
APC NM_001127510.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 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 · 3
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, the APC panel's designated population dataset.
The APC InSiGHT specification directs PM2 assessment using the total population from the gnomAD v2.1.1 non-cancer dataset and assigns PM2 at supporting strength only. Its rarity rule is AF <=0.000003 when allele count is >1, or AF <0.00001 when allele count is <=1.gnomAD v2.1 reports the variant absent.gnomAD v4.1 reports 5/1,612,964 alleles (total AF 3.09988e-06), joint grpmax FAF 7.9e-07, highest raw subpopulation AF 3.38249e-05 (1/29,564 Ashkenazi Jewish alleles), and zero homozygotes.
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
✓
BP4 supporting Benign
Met (Supporting): SpliceAI max delta 0.00 predicts no splice impact, indicating no effect on gene or gene product.
APC CSPEC v2.1 BP4 rule: 'Missense variants: BP4 is not applicable. Synonymous (silent) or intronic variants: Multiple in silico splicing predictors suggest no impact on gene or gene product.'SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).'REVEL lookup for this variant returned found: false / revel_score: null, so no REVEL-based missense evidence exists (and is inapplicable given synonymous consequence).
cspec ↗spliceai ↗
✓
BP7 supporting Benign
Met (Supporting): synonymous change with SpliceAI max delta 0.00 predicts no splice-consensus disruption or new splice site.
APC CSPEC v2.1 BP7 strength rule: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.'APC CSPEC v2.1 BP7 instructionsToUse: 'The use of BP7 with BP4 is allowed.'SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).'
cspec ↗spliceai ↗
Assessed · not applied · 3 not met · 10 not assessed
Pathogenic
PS2 Not assessed: no de novo occurrence in an affected proband with confirmed parentage is documented.
PS3 Not assessed: no RNA or protein functional assay of this variant was available.
PS4 Not assessed: no affected-proband observations or case-control enrichment data were available.
PM6 Not assessed: no presumed de novo occurrence with unconfirmed parental relationships is documented.
PP1 Not assessed: no family segregation data were available for this variant.
PP3 Not met: SpliceAI max delta 0.00 predicts no splice impact, below the threshold for a deleterious-splicing call.
Benign
BA1 Not met: gnomAD filtering allele frequency 7.9e-07 (0.000079%) versus the required >=0.1% threshold.
BS1 Not met: gnomAD filtering allele frequency 7.9e-07 (0.000079%) versus the required >=0.001% threshold.
BS2 Not assessed: no healthy-individual observations or homozygotes were available.
BS3 Not assessed: no RNA assay demonstrating normal splicing of this variant was available.
BS4 Not assessed: no informative non-segregation evidence was available.
BP2 Not assessed: no co-occurrence data with a pathogenic APC variant were available.
BP5 Not assessed: no evidence established an alternate genetic basis for the phenotype.
N/A · 12 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09988e-06; MAF= 0.00031%, 5/1612964 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.38249e-05; MAF= 0.00338%, 1/29564 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031% · 5 / 1,612,964
0 hom · FAF 7.9e-05%
Ashkenazi Jewish
1 / 29,564
0.0034%
European (non-Finnish)
4 / 1,179,422
0.00034%
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American)
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 482261)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
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 · 7 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
20301519 ↗ APC-Associated Polyposis Conditions. CLINVAR
21368914 ↗ Clinical utility gene card for: familial adenomatous polyposis (FAP) and attenuated FAP (AFAP). CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR
35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR