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 encodes a tumor-suppressor brake on Wnt signaling, and inherited APC loss-of-function variants cause autosomal dominant familial adenomatous polyposis and colorectal cancer risk.
Likely Benign: BS1 strong is met because gnomAD v4.1 Popmax filtering AF 0.00023147 exceeds the APC VCEP threshold of 0.00001. Likely Benign: BP1 supporting is met because codon 1413 lies outside the APC VCEP exception covering codons 1021-1035.
BS1 + BP1→Likely Benign
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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 · 16 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
✓
BS1strongBenign
Met, strong: gnomAD v4.1 Popmax filtering AF 0.00023147 exceeds the APC VCEP BS1 threshold of 0.00001.
The APC InSiGHT VCEP version 2.1 specifies BS1 Strong as gnomAD Popmax Filtering Allele Frequency >= 0.001% (0.00001).gnomAD v4.1 reports Popmax filtering AF 0.00023147, based on the joint dataset; this exceeds 0.00001. gnomAD v2.1 also reports grpmax FAF 0.00020478.
Met, supporting: codon 1413 lies outside the APC VCEP BP1 exception covering only the first repeat at codons 1021-1035.
The APC VCEP BP1 rule is applicable to APC missense variants except those in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.The assessed protein change is p.Met1413Val, placing the residue at codon 1413, outside the codon 1021-1035 exception.
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1Not met: c.4237A>G is a missense variant causing p.Met1413Val, not an APC null variant eligible for the VCEP PVS1 decision tree.
PS1Not met: p.Met1413Val is not one of the APC VCEP's two established likely pathogenic missense comparators, p.Asn1026Ser or p.Ser1028Arg.
PS2Not assessed: no documented confirmed maternity-and-paternity testing or validated de novo observation is available for the proband.
PS3Not assessed: no variant-specific functional assay demonstrates that APC p.(Met1413Val) damages protein function or splicing under the APC VCEP criteria.
PS4Not met: M1413V occurred in one polyposis patient and three healthy controls, without a qualifying phenotype-point total or case-control enrichment estimate.
PM2Not met: gnomAD v4.1 AF 0.000216837 from 350/1,614,118 alleles exceeds the APC VCEP PM2 threshold of 0.000003 for allele count above one.
PM5Not assessed: no qualifying alternate missense comparator at residue 1413 was identified, and same-residue retrieval ended with an HTTP 429 rate-limit error.
PM6Not assessed: the evidence does not report an apparently de novo proband or parental testing sufficient to assign any PM6 de novo score.
PP1Not assessed: the reports provide no qualifying count of affected meioses, while M1413V was also observed in unaffected relatives and healthy controls.
PP3Not met: REVEL 0.587 is below the >=0.644 supporting PP3 threshold for missense variants.
Benign
BA1Not met: gnomAD v4.1 Popmax filtering AF 0.00023147 is below the APC VCEP BA1 threshold of 0.001.
BS2Not met: gnomAD reports 0 homozygotes, while three healthy-control observations provide only 1.5 APC VCEP points versus the 3-point BS2 Supporting threshold.
BS3Not assessed: no variant-specific assay shows APC p.(Met1413Val) retains wild-type function or normal RNA processing under the APC VCEP criteria.
BS4Not assessed: unaffected carriers and healthy controls are reported, but no affected noncarrier meeting the APC phenotype-point threshold is documented.
BP2Not assessed: one patient had M1413V plus a premature-termination APC variant, but phase was not established and the VCEP requires trans or at least three unknown-phase observations.
BP5Not met: no (Likely) Pathogenic variant in another adenomatous polyposis gene is documented, and the reported second variant was also in APC.
This variant is present in gnomAD v4.1 (AF= 0.000216837; MAF= 0.02168%, 350/1614118 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000303961; MAF= 0.03040%, 19/62508 alleles, homozygotes = 0); grpmax FAF= 0.00023147.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000198295; MAF= 0.01983%, 56/282408 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.00035828; MAF= 0.03583%, 9/25120 alleles, homozygotes = 0); grpmax FAF= 0.00020478.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.022%
· 350 / 1,614,118
0 hom · FAF 0.023%
Remaining individuals
19 / 62,508
0.03%
European (non-Finnish)
302 / 1,180,010
0.026%
European (Finnish)
15 / 64,032
0.023%
Admixed American
8 / 60,004
0.013%
African/African American
6 / 75,038
0.008%
+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.02%
· 56 / 282,408
0 hom · FAF 0.02%
European (Finnish)
9 / 25,120
0.036%
European (non-Finnish)
36 / 128,792
0.028%
Admixed American
9 / 35,428
0.025%
Remaining individuals
1 / 7,206
0.014%
African/African American
1 / 24,954
0.004%
+ 3 not observed (Ashkenazi Jewish, East Asian, South Asian)
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 133510)
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57371565, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
