Classification rationale

BA1BS1 Benign

APC c.3374T>C missense · exon 17

BA1 (Stand-alone): East Asian popmax allele frequency 0.823% (gnomAD v2.1) and 0.379% (v4.1) exceeds the >=0.1% stand-alone benign threshold. BS1 (Strong): formally met at >=0.001%, but it is the same population observation as BA1 and adds no independent evidence. Benign overall: the InSiGHT APC VCEP v2.1 Rule 26 stand-alone rule terminates classification as Benign once BA1 is met.

BA1 + BS1 → Benign

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

APC NM_001127510.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 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

BA1 stand-alone Benign

Met (stand-alone): gnomAD East Asian popmax allele frequency 0.823% (v2.1) and 0.379% (v4.1) exceeds the >=0.1% BA1 threshold by 3- to 8-fold.

APC VCEP v2.1 (cspec): BA1 rule states 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001)' at Stand Alone strength; instructions recommend the non-cancer dataset from gnomAD v2.1.1.gnomad_v2 (gnomAD v2.1, GRCh37 5-112174665-T-C): overall AF 0.000599 (0.0599%; 169/282,016 alleles, 1 homozygote); East Asian popmax AF 0.00823 (0.823%; 164/19,922 alleles, 1 homozygote); exome grpmax FAF 0.00700 (0.700%).gnomad_v4 (gnomAD v4.1, GRCh38 5-112838968-T-C): overall AF 0.000131 (0.0131%; 211/1,613,984 alleles, 0 homozygotes); East Asian popmax AF 0.00379 (0.379%; 170/44,878 alleles); joint grpmax FAF 0.00332 (0.332%).

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 strong Benign

Met (strong): the same East Asian popmax frequencies (0.823% v2.1, 0.379% v4.1) exceed the >=0.001% BS1 threshold by several hundred-fold. Same observation as BA1, so not independent evidence.

APC VCEP v2.1 (cspec): BS1 rule states 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001)' at Benign Strong strength; instructions recommend the non-cancer dataset from gnomAD v2.1.1.gnomad_v2: East Asian popmax AF 0.00823 (0.823%) and exome grpmax FAF 0.00700 (0.700%), far above the 0.001% BS1 threshold.gnomad_v4: East Asian popmax AF 0.00379 (0.379%) and joint grpmax FAF 0.00332 (0.332%), far above the 0.001% BS1 threshold.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 5 not met · 13 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to determine whether an established pathogenic variant produces the same amino-acid change.

PS2 Not assessed: insufficient evidence was available to confirm a de novo origin.

PS3 Not assessed: insufficient evidence was available from functional studies to judge impact on protein function.

PS4 Not met: no case-control enrichment - p.V1125A occurred in 3 of 80 Taiwanese CRC patients versus 1 of 74 controls, a non-significant difference.

PM1 Not assessed: insufficient evidence was available to determine whether this position is a mutational hotspot or critical functional domain.

PM2 Not met: gnomAD v4.1 overall allele frequency 0.0131% is ~44-fold above the PM2 ceiling of <=0.0003%, so the variant is far from rare.

PM3 Not assessed: insufficient evidence was available to evaluate this criterion.

PM5 Not assessed: insufficient evidence was available to determine whether a different pathogenic missense change is known at this residue.

PM6 Not assessed: insufficient evidence was available to determine whether the variant arose de novo.

PP1 Not assessed: insufficient evidence was available to evaluate co-segregation with disease in affected relatives.

PP2 Not assessed: insufficient evidence was available to evaluate this criterion.

PP3 Not met: the APC VCEP permits only splicing predictions for missense variants, and SpliceAI reports max delta 0.00 - no predicted splicing impact.

Benign

BS2 Not met: roughly 0.5-1 healthy-individual point (one of 74 Taiwanese controls) and a single gnomAD homozygote fall short of the >=3 points or >=2 homozygotes required.

BS3 Not assessed: insufficient evidence was available from functional studies to determine whether the variant lacks a damaging effect.

BS4 Not assessed: insufficient evidence was available to evaluate segregation among affected family members.

BP1 Not assessed: insufficient evidence was available to evaluate this criterion.

BP2 Not assessed: insufficient evidence was available to evaluate this criterion.

BP5 Not met: no documented pathogenic variant in another polyposis gene (e.g., biallelic MUTYH or POLD1/POLE) was found in any p.Val1125Ala carrier.

N/A · 8 PVS1 · PM4 · 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= 0.000130732; MAF= 0.01307%, 211/1613984 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00378805; MAF= 0.37880%, 170/44878 alleles, homozygotes = 0); grpmax FAF= 0.00332268.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000599257; MAF= 0.05993%, 169/282016 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00823211; MAF= 0.82321%, 164/19922 alleles, homozygotes = 1); grpmax FAF= 0.00700099.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0009231103388357949, 17/18416 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.013% · 211 / 1,613,984
0 hom · FAF 0.33%

East Asian 170 / 44,878	0.38%
Remaining individuals 37 / 62,484	0.059%
Admixed American 2 / 59,998	0.0033%
African/African American 1 / 74,908	0.0013%
European (non-Finnish) 1 / 1,180,020	8.5e-05%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.06% · 169 / 282,016
1 hom · FAF 0.7%

East Asian 164 / 19,922	0.82% 1 hom
Remaining individuals 4 / 7,198	0.056%
African/African American 1 / 24,876	0.004%

+ 5 not observed (Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian)

gnomAD Canada 🇨🇦

0.092% · 17 / 18,416
0 hom · FAF 0.75%

East Asian 16 / 1,338	1.2%
Remaining individuals 1 / 1,138	0.088%

+ 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 132749)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.328746.

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; COSV57340743, n = 4 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

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national s CLINVAR

16569251 ↗ Single nucleotide polymorphisms of the APC gene and colorectal cancer risk: a case-control study in Taiwan. CLINVAR

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

21859464 ↗ Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? CLINVAR

22138009 ↗ NCCN Task Force report: Evaluating the clinical utility of tumor markers in onco CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting CLINVAR

25373533 ↗ Updated guidelines for biomarker testing in colorectal carcinoma: a national con CLINVAR

25479140 ↗ Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. CLINVAR