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NM_000038.6:c.2677G>A
p.Glu893Lys · APC
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 · v2.1
0%
complete
Final classification
VUS
BP1
APC
c.2677G>A
p.Glu893Lys
missense · exon 16
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 encodes a tumor-suppressor protein that restrains Wnt signaling, and inherited APC alterations cause autosomal-dominant familial adenomatous polyposis with high colorectal cancer risk.

Transcript
NM_000038.6
HGVS · transcript:coding
NM_000038.6:c.2677G>A
GRCh38
chr5:112838271 G>A
GRCh37
chr5:112173968 G>A
VUS: only BP1 (supporting) was met, and the APC InSiGHT VCEP Version 2.1 criteria-combination framework matched no classification rule.
Classification rationale
BP1 VUS
APC c.2677G>A missense · exon 16

BP1 supporting: APC codon 893 lies outside the VCEP exception at codons 1021-1035.

BP1 → VUS
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_000038.6 · variants mapped to exon structure
APC NM_000038.6
Fetching transcript structure from UCSC…
Applied criteria · 1 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 · 1
Strength Supporting Moderate Strong Very strong
BP1 supporting Benign
Met, supporting: APC codon 893 lies outside the VCEP BP1 exception at codons 1021-1035.
The APC VCEP BP1 rule applies to APC missense variants except codons 1021-1035, and the assessed variant is p.Glu893Lys at codon 893.
cspec ↗
Assessed · not applied · 2 not met · 14 not assessed
Pathogenic
PS1 Not met: the APC specification identifies only p.Asn1026Ser and p.Ser1028Arg as likely pathogenic missense comparators, not p.Glu893Lys.
PS2 Not assessed: no documented parental genotypes, confirmed maternity and paternity, affected phenotype, or APC VCEP de novo score is available.
PS3 Not assessed: no variant-specific RNA or validated damaging protein assay was identified for p.(Glu893Lys), which lies outside the APC beta-catenin-binding domain at codons 959-2129.
PS4 Not assessed: no exact-variant case-control enrichment or patient phenotype-point data are available to compare with the APC VCEP PS4 thresholds.
PM2 Not assessed: the VCEP requires non-cancer AF, while only combined values of 2.39238e-05 and 2.23035e-05 are available.
PM5 Not assessed: zero same-residue candidates were found, but the comparator search recorded an HTTP 429 error and cannot exclude a qualifying p.Glu893 variant.
PM6 Not assessed: no assumed-de-novo observation, phenotype point, parental testing status, or APC VCEP de novo score is documented.
PP1 Not assessed: no affected relatives, variant-positive family members, family count, or segregating meiosis count is documented.
PP3 Not met: missense REVEL 0.617 is below the >=0.644 supporting PP3 threshold, and the SpliceAI score cannot substitute for the applicable REVEL path.
Benign
BA1 Not assessed: the APC VCEP requires non-cancer Popmax AF, but only all-comers values (2.302e-05 and 1.994e-05) are available.
BS1 Not assessed: the APC VCEP requires non-cancer Popmax AF, although available all-comers values (2.302e-05 and 1.994e-05) exceed 0.00001.
BS2 Not assessed: no qualifying healthy individuals or VCEP-required non-cancer homozygote count is available; combined datasets report zero homozygotes but are not sufficient.
BS3 Not assessed: p.(Glu893Lys) is a codon-893 missense variant with no qualifying benign RNA or protein assay under the APC VCEP BS3 requirements.
BS4 Not assessed: no affected relative lacking the variant has a documented APC phenotype point of at least 0.5.
BP2 Not assessed: no qualifying trans observation or at least three unknown-phase observations with different (Likely) Pathogenic APC variants are documented.
BP5 Not assessed: no alternate-gene Pathogenic/Likely pathogenic variant and no documented colorectal-polyposis phenotype are available for the APC VCEP BP5 rule.
N/A · 11 PVS1 · PM1 · PM3 · PM4 · PP2 · PP4 · PP5 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
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= 2.23035e-05; MAF= 0.00223%, 36/1614100 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.80092e-05; MAF= 0.00480%, 3/62488 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 2.39238e-05; MAF= 0.00239%, 6/250796 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.30157e-05; MAF= 0.00530%, 6/113174 alleles, homozygotes = 0); grpmax FAF= 2.302e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0022% · 36 / 1,614,100
0 hom · FAF 0.002%
Remaining individuals
3 / 62,488
0.0048%
European (non-Finnish)
33 / 1,180,050
0.0028%
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0024% · 6 / 250,796
0 hom · FAF 0.0023%
European (non-Finnish)
6 / 113,174
0.0053%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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 Uncertain significance (7 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 41501)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.617. BayesDel score = 0.149074.
SpliceAI ↗
Functional / OncoKB screenshot
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 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 previously been reported in somatic cancers (COSMIC; COSV57384932, 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
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
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
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR
26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR
34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and geno CLINVAR