0%
APCc.2677G>AUncertain significance
Print report
Variant interpretation report

APC c.2677G>A, p.(Glu893Lys)

NM_000038.6:c.2677G>A NP_000029.2:p.(Glu893Lys) Missense · exon 16 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About APC

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.

NCBI Gene ↗ OncoKB ↗
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.
01The reasoning

How it was classified

The recorded framework is ClinGen APC VCEP v2.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Supporting
BP1 · supporting

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

Recorded classification: Uncertain significance

VUS: only BP1 (supporting) was met, and the APC InSiGHT VCEP Version 2.1 criteria-combination framework matched no classification rule.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
36 / 1,614,100 alleles

gnomAD v4.1: 36 / 1,614,100 alleles. Recorded AF 2.23035e-05. Recorded homozygote count 0.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.617 recorded score

Recorded REVEL score: 0.617. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
10 reported laboratory submissions

7 Uncertain significance · 2 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57384932, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen APC VCEP v2.1, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 2 not met · 14 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The APC InSiGHT VCEP governs this case. PP4, PP5, and BP6 are explicitly not applicable; PS4 requires APC phenotype-point data that are absent; BP5 requires an alternate pathogenic genetic basis plus colorectal polyposis, neither documented here.

No numeric criterion threshold was adjudicated because the available evidence contains no PS4 enrichment estimate or BP5 numeric rule.

For NM_000038.6:c.2677G>A (p.Glu893Lys), PP3 is not met because the applicable missense REVEL score is 0.617, while BP4 and BP7 are not applicable under their variant-scope rules.

Met · 1

BP1 SupportingMet, supporting: APC codon 893 lies outside the VCEP BP1 exception at codons 1021-1035. Details ▾Hide ▴
Reasoning

The APC VCEP states that BP1 is applicable to APC missense variants except those located in the first 15-amino-acid repeat of the beta-catenin-binding domain, defined as codons 1021-1035. The assessed missense variant is p.Glu893Lys at codon 893, outside that exception, so BP1 is met at supporting strength.

Rule
APC VCEP BP1: applicable to APC missense variants except variants in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.
Evidence considered
  • The APC VCEP BP1 rule applies to APC missense variants except codons 1021-1035, and the assessed variant is p.Glu893Lys at codon 893.
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

PS1 Not met: the APC specification identifies only p.Asn1026Ser and p.Ser1028Arg as likely pathogenic missense comparators, not p.Glu893Lys. Details ▾Hide ▴
Reasoning

The APC VCEP permits PS1 for a missense variant only when the same amino-acid change was previously established as pathogenic or likely pathogenic. The assessed variant is NP_000029.2:p.(Glu893Lys). The governing specification identifies only c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg) as currently likely pathogenic APC missense variants, and states that no APC missense variant has been classified as pathogenic on current evidence. Neither is the same amino-acid change or residue as p.Glu893Lys, so PS1 is not met.

Rule
APC VCEP PS1: same amino-acid change as a previously established pathogenic or likely pathogenic variant; the specification lists p.Asn1026Ser and p.Ser1028Arg as the only current likely pathogenic APC missense variants.
Evidence considered
  • The APC VCEP specification limits PS1 to a previously established pathogenic or likely pathogenic same-amino-acid change and lists only p.Asn1026Ser and p.Ser1028Arg as current likely pathogenic missense variants; neither matches p.Glu893Lys.
Sources
cspec ↗
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. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000038.6:c.2677G>A (p.Glu893Lys), so the applicable calibrated computational path is REVEL rather than SpliceAI. REVEL is 0.617, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997). The APC VCEP specifies PP3 at Supporting strength and directs that presumed missense variants be evaluated with in silico splicing predictors for possible splicing effects; however, no VCEP lookup or other supporting material directly pre-assigns PP3 for this variant, and the supplied missense-path rule prohibits substituting the SpliceAI result for the below-threshold REVEL score. BayesDel is not used because no applicable APC cutoff is specified and no generic ACMG-strength calibration is established.

Rule
APC VCEP Version 2.1 PP3 Supporting: Missense variants should not use computational prediction models for conservation or evolution; in silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The local REVEL lookup reports a score of 0.617 for GRCh38 chr5:112838271 G>A.
  • The supplied ClinGen SVI REVEL calibration sets supporting PP3 at >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The APC Version 2.1 VCEP specifies PP3 as Supporting and states for missense variants that in silico splicing predictors should be used to reveal possible splicing effects; no variant-specific pre-assigned PP3 code is present in the governing materials.
  • The available BayesDel score is not used because the supplied instructions establish no generic ACMG-strength calibration for BayesDel and the APC VCEP supplies no applicable BayesDel cutoff.
Sources
cspec ↗revel

Not assessed · 14 · no assessment recorded

PS2 Not assessed: no documented parental genotypes, confirmed maternity and paternity, affected phenotype, or APC VCEP de novo score is available. Details ▾Hide ▴
Reasoning

The APC VCEP requires confirmed de novo status in an affected patient without a family history and assigns strength from de novo scores: moderate for 1–1.5, strong for 2–3.5, and very strong for at least 4. The available exact-match record provides no documented proband phenotype, maternity and paternity confirmation, parental genotypes, or de novo score, so PS2 cannot be assessed.

Rule
APC VCEP PS2: very strong for ≥4 de novo scores, strong for 2–3.5, and moderate for 1–1.5; de novo requires both maternity and paternity confirmation in an affected patient without family history.
Evidence considered
  • The APC Version 2.1 specification requires confirmed maternity and paternity for PS2 and scores de novo observations using its phenotype-point and parental-relationship table.
  • The exact-match ClinVar record contains no usable report of parental testing, de novo status, or a de novo score for NM_000038.6:c.2677G>A (p.Glu893Lys).
Still missing
  • Documented affected-proband phenotype consistent with APC-associated polyposis
  • Maternal and paternal relationship confirmation
  • Both parental genotypes at NM_000038.6:c.2677G>A
  • APC VCEP de novo score
Sources
cspec ↗clinvar ↗
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. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification requires qualifying RNA evidence for aberrant transcript consequences or, at supporting strength, a protein assay showing increased beta-catenin-regulated transcription or decreased beta-catenin binding within the beta-catenin-binding domain (codons 959-2129). NM_000038.6:c.2677G>A is a missense variant encoding p.(Glu893Lys), outside that domain, and the reviewed case evidence contains no variant-specific RNA or validated protein functional assay demonstrating a damaging effect. Computational predictions and the absence of variant-specific functional review in OncoKB do not satisfy PS3.

Rule
APC VCEP PS3: RNA assays must demonstrate the specified abnormal transcript consequences; supporting protein assays require increased beta-catenin-regulated transcription and/or decreased beta-catenin binding for variants within APC codons 959-2129.
Evidence considered
  • The APC InSiGHT VCEP PS3 rule specifies RNA evidence showing a premature stop, relevant exon skipping, or an alternative transcript, and at supporting strength permits protein evidence of increased beta-catenin-regulated transcription or decreased beta-catenin binding only for variants in codons 959-2129.
  • The variant is a missense substitution, NM_000038.6:c.2677G>A, NP_000029.2:p.(Glu893Lys), at codon 893; no variant-specific RNA or protein assay result is present in the case evidence.
  • OncoKB reports no variant-specific reviewed functional evidence for this variant.
  • The reviewed literature extracts for PMID:22703879 report no variant-specific functional data for APC c.2677G>A, and PMID:25741868 provides only general functional-study guidance rather than an assay of this variant.
Still missing
  • A validated, biologically relevant assay for p.(Glu893Lys) demonstrating abnormal APC function or splicing is unavailable.
  • No reproducible clinical-laboratory functional validation or appropriate assay controls were identified.
Sources
cspec ↗oncokb ↗PMID:25741868 ↗PMID:22703879 ↗
PS4 Not assessed: no exact-variant case-control enrichment or patient phenotype-point data are available to compare with the APC VCEP PS4 thresholds. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PS4 from phenotype points: ≥16 for Very Strong, 4-15.5 for Strong, 2-3.5 for Moderate, and 1-1.5 for Supporting, with phenotype points curated from Table 1. The available evidence does not document this exact variant in affected individuals, a case-control enrichment estimate, or patient-level phenotype features from which phenotype points can be assigned. Therefore PS4 cannot be assessed rather than inferred from APC disease descriptions or non-variant-specific literature.

Rule
APC InSiGHT VCEP PS4: ≥ 16 phenotype points = Very Strong; 4-15.5 = Strong; 2-3.5 = Moderate; 1-1.5 = Supporting; phenotype points are curated from Table 1.
Evidence considered
  • The APC InSiGHT VCEP rule states: ≥ 16 phenotype points supports PS4 Very Strong; 4-15.5 supports Strong; 2-3.5 supports Moderate; and 1-1.5 supports Supporting, with phenotype points curated using Table 1.
  • The extracted literature does not mention APC c.2677G>A/p.(E893K) as an affected-patient variant. PMID:22703879 reports an APC variant-count table from 572 exomes but supplies no variant-specific case, segregation, or phenotype data for c.2677G>A.
  • PMID:15604628 and PMID:25394175 describe general FAP phenotype or referral features, but do not establish that this exact variant occurred in affected individuals or provide a PS4 case-control comparison.
Still missing
  • Exact-variant affected-individual count and phenotype details are not documented.
  • No case-control odds ratio or relative risk with confidence interval is available.
  • No APC VCEP Table 1 phenotype-point total can be calculated.
Sources
cspec ↗PMID:15604628 ↗PMID:25394175 ↗PMID:22703879 ↗
PM2 Not assessed: the VCEP requires non-cancer AF, while only combined values of 2.39238e-05 and 2.23035e-05 are available. Details ▾Hide ▴
Reasoning

The governing APC InSiGHT VCEP specifies the total population from the gnomAD v2.1.1 non-cancer dataset for PM2 and applies PM2 Supporting when AF is <=0.000003 with allele count >1 or <0.00001 with allele count <=1. The required non-cancer allele count and AF are absent. Available combined/all-comers data show 6/250796 (2.39238e-05) in gnomAD v2.1 and 36/1614100 (2.23035e-05) in gnomAD v4.1, but those cannot substitute for the VCEP-specified source.

Rule
Rare in controls: AF <=0.0003% (0.000003) if allele count >1 OR AF <0.001% (0.00001) if allele count <=1; use the total population from the non-cancer gnomAD v2.1.1 dataset.
Evidence considered
  • The APC InSiGHT VCEP specifies the total population from the gnomAD v2.1.1 non-cancer dataset for PM2.
  • The VCEP PM2 Supporting rule is AF <=0.000003 when allele count is >1 or AF <0.00001 when allele count is <=1.
  • Combined/all-comers gnomAD values are available, but the required non-cancer subset is absent; therefore those values were not used to adjudicate PM2.
Still missing
  • Required gnomAD v2.1.1 non-cancer exome allele count, allele number, and allele frequency are not present in the case evidence.
Sources
cspec ↗
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. Details ▾Hide ▴
Reasoning

The APC VCEP PM5 rule requires a different missense change at the same amino-acid residue, established as likely pathogenic or pathogenic under APC-specific modifications, with an equal or higher Grantham distance. The available PM5 candidate collection found zero same-residue candidates for p.Glu893Lys, but the collection also records an HTTP 429 retrieval error; therefore the evidence is insufficient to conclude that no qualifying p.Glu893 comparator exists.

Rule
APC VCEP PM5: different missense variant at the same amino-acid residue established as likely pathogenic or pathogenic, with Grantham distance equal to or greater than the assessed variant.
Evidence considered
  • The APC VCEP requires a different missense change at the same residue, established as likely pathogenic or pathogenic under APC-specific modifications, and an equal or higher Grantham distance.
Still missing
  • A complete, rate-limit-resilient search for independently established pathogenic or likely pathogenic alternate missense variants at APC residue 893, including Grantham-distance comparison, is still needed.
Sources
cspec ↗pm5_candidates
PM6 Not assessed: no assumed-de-novo observation, phenotype point, parental testing status, or APC VCEP de novo score is documented. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PM6 from de novo scores when paternity and/or maternity are not confirmed: supporting for 0.5, moderate for 1–1.5, and strong for 2–3.5. No case-level report documents an assumed de novo observation, phenotype point, parental genotypes, or de novo score for this variant, so PM6 cannot be assessed.

Rule
APC VCEP PM6: supporting for 0.5 de novo score, moderate for 1–1.5, and strong for 2–3.5; curate de novo scores using APC Tables 1 and 2.
Evidence considered
  • The APC Version 2.1 specification defines PM6 as assumed de novo without confirmed paternity and/or maternity and assigns strength from 0.5 to 3.5 de novo scores.
  • The exact-match ClinVar record does not provide a case-level assumed-de-novo statement, parental testing details, phenotype point, or de novo score for NM_000038.6:c.2677G>A (p.Glu893Lys).
Still missing
  • Case-level evidence that the variant was considered de novo
  • Affected-proband phenotype point under APC Table 1
  • Parental testing status
  • APC VCEP de novo score
Sources
cspec ↗clinvar ↗
PP1 Not assessed: no affected relatives, variant-positive family members, family count, or segregating meiosis count is documented. Details ▾Hide ▴
Reasoning

The APC VCEP requires affected relatives with the variant and assigns supporting strength for 3–4 segregating meioses, moderate for 5–6, and strong for at least 7 meioses in at least 2 families. No family members, affected-relative phenotypes, variant genotypes, family count, or meiosis count are documented, so PP1 cannot be assessed.

Rule
APC VCEP PP1: supporting for 3–4 segregating meioses in at least 1 family, moderate for 5–6 in at least 1 family, and strong for ≥7 in at least 2 families; count only genotype- and phenotype-positive individuals or qualifying obligate carriers.
Evidence considered
  • The APC Version 2.1 specification defines PP1 strength by informative segregating meioses: 3–4 supporting, 5–6 moderate, and ≥7 in ≥2 families strong.
  • The exact-match ClinVar record and extracted literature provide no variant-specific pedigree, affected-relative genotype, phenotype-point, family-count, or meiosis-count data.
Still missing
  • Pedigree with affected relatives
  • Variant status for each informative relative
  • Phenotype evidence meeting APC VCEP points for affected relatives
  • Number of informative segregating meioses and families
Sources
cspec ↗clinvar ↗
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. Details ▾Hide ▴
Reasoning

The governing APC InSiGHT VCEP specifies use of the gnomAD non-cancer dataset and a Popmax filtering AF threshold of >=0.001 (0.1%) for BA1. The case materials provide only combined/all-comers gnomAD v2.1 and v4.1 data, not the required non-cancer subset, so BA1 cannot be adjudicated under the governing specification. The available all-comers Popmax filtering AFs (2.302e-05 in gnomAD v2.1 and 1.994e-05 in gnomAD v4.1) are below the VCEP threshold but cannot substitute for the specified source.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001); use the non-cancer dataset from gnomAD v2.1.1.
Evidence considered
  • The APC InSiGHT VCEP specifies the non-cancer gnomAD dataset for BA1 and defines BA1 as gnomAD Popmax filtering AF >=0.001 (0.1%).
  • Combined/all-comers gnomAD values are available, but the required non-cancer subset is absent; therefore those values were not used to adjudicate BA1.
Still missing
  • Required gnomAD v2.1.1 non-cancer exome Popmax filtering allele frequency is not present in the case evidence.
Sources
cspec ↗
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. Details ▾Hide ▴
Reasoning

The governing APC InSiGHT VCEP specifies use of the gnomAD non-cancer dataset and a Popmax filtering AF threshold of >=0.00001 (0.001%) for BS1. The case materials provide only combined/all-comers gnomAD v2.1 and v4.1 data, not the required non-cancer subset, so BS1 cannot be adjudicated under the governing specification. The available all-comers Popmax filtering AFs (2.302e-05 in gnomAD v2.1 and 1.994e-05 in gnomAD v4.1) exceed the threshold but cannot substitute for the specified source.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001); use the non-cancer dataset from gnomAD v2.1.1.
Evidence considered
  • The APC InSiGHT VCEP specifies the non-cancer gnomAD dataset for BS1 and defines BS1 as gnomAD Popmax filtering AF >=0.00001 (0.001%).
  • Combined/all-comers gnomAD values are available, but the required non-cancer subset is absent; therefore those values were not used to adjudicate BS1.
Still missing
  • Required gnomAD v2.1.1 non-cancer exome Popmax filtering allele frequency is not present in the case evidence.
Sources
cspec ↗
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. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits BS2 at strong strength for at least two homozygous observations or at least 10 qualifying healthy-individual points, and specifically permits the gnomAD v2.1.1 non-cancer dataset to search for homozygotes. The case materials contain no qualifying healthy-individual observations and no required non-cancer homozygote count. Although combined/all-comers gnomAD v2.1 and v4.1 report zero homozygotes, those are not the VCEP-specified non-cancer subset and cannot establish BS2 under this rule.

Rule
>=10 points for healthy individuals OR >=2 observations in the homozygous state; gnomAD v2.1.1 non-cancer data may be used to search for homozygotes, but not for heterozygous healthy individuals.
Evidence considered
  • The APC InSiGHT VCEP defines BS2 Strong as >=10 healthy-individual points or >=2 homozygous observations.
  • The VCEP states that gnomAD v2.1.1 non-cancer data may be used to search for homozygous individuals, but that required subset is absent from the case materials.
  • Combined/all-comers gnomAD v2.1 and v4.1 report zero homozygotes, but those values were not treated as the specified non-cancer BS2 evidence.
Still missing
  • Required gnomAD v2.1.1 non-cancer homozygote count is not present.
  • No qualifying APC-specific healthy-individual observations or point totals are available.
Sources
cspec ↗
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. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification permits BS3 strong only for a constitutional RNA assay of a synonymous or intronic variant showing no mRNA aberration with biallelic expression or nonsense-mediated-decay inhibition, and permits BS3 supporting for the same RNA context without those controls or for a protein assay showing retained beta-catenin-regulated transcription comparable to wild type within codons 959-2129. NM_000038.6:c.2677G>A is a missense variant at codon 893, and no qualifying benign RNA or protein assay was identified; therefore BS3 cannot be applied from the available evidence.

Rule
APC VCEP BS3: strong requires a constitutional RNA assay of a synonymous or intronic variant with no mRNA aberration plus biallelic expression and/or nonsense-mediated-decay inhibition; supporting permits that RNA evidence without those controls or retained wild-type-like beta-catenin-regulated transcription for variants in codons 959-2129.
Evidence considered
  • The APC InSiGHT VCEP BS3 rule requires either a qualifying constitutional RNA assay for a synonymous or intronic variant, with specified controls for strong strength, or a protein assay showing beta-catenin-regulated transcription comparable to wild type for variants within codons 959-2129.
  • This variant is the missense substitution NM_000038.6:c.2677G>A, NP_000029.2:p.(Glu893Lys), at codon 893; the available evidence contains no qualifying benign functional assay.
  • OncoKB reports no variant-specific reviewed functional evidence for this variant.
  • The reviewed literature extracts for PMID:22703879 report no variant-specific functional data for APC c.2677G>A, while PMID:25741868 describes general requirements for biologically relevant, validated, reproducible functional studies without studying this variant.
Still missing
  • No validated assay demonstrates retained normal APC function or normal splicing for p.(Glu893Lys).
  • No assay-control data, biallelic-expression evidence, or nonsense-mediated-decay control relevant to this variant were identified.
Sources
cspec ↗oncokb ↗PMID:25741868 ↗PMID:22703879 ↗
BS4 Not assessed: no affected relative lacking the variant has a documented APC phenotype point of at least 0.5. Details ▾Hide ▴
Reasoning

The APC VCEP requires an affected family member without the variant who meets a phenotype threshold: supporting for at least 0.5 phenotype point, or strong for one member with at least 1 point or two members each with at least 0.5 point. No such relatives or phenotype assessments are documented, so BS4 cannot be assessed.

Rule
APC VCEP BS4: strong when one affected member without the variant scores ≥1 phenotype point or two each score ≥0.5; supporting when one affected member without the variant scores ≥0.5.
Evidence considered
  • The APC Version 2.1 specification defines BS4 supporting at ≥0.5 phenotype point in one affected non-carrier and BS4 strong at ≥1 point in one or ≥0.5 point in two affected non-carriers.
  • No affected non-carrier, genotype result, APC phenotype-point assessment, phenocopy evaluation, or alternate pathogenic variant is documented in the exact-match ClinVar evidence or extracted literature.
Still missing
  • Affected relative without NM_000038.6:c.2677G>A
  • Reliable genotype result for the non-carrier affected relative
  • APC phenotype features and phenotype-point calculation
  • Assessment for phenocopy or a second pathogenic variant
Sources
cspec ↗clinvar ↗
BP2 Not assessed: no qualifying trans observation or at least three unknown-phase observations with different (Likely) Pathogenic APC variants are documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits BP2 at supporting strength when the variant is observed in trans with a (Likely) Pathogenic APC variant, or at least three times in an unknown phase with different (Likely) Pathogenic APC variants. The available evidence does not document a qualifying trans observation, cis observation that would exclude trans, or three qualifying unknown-phase observations; therefore BP2 cannot be applied.

Rule
BP2 Supporting: observed in trans with a (Likely) Pathogenic APC variant, or observed at least three times in an unknown phase with different (Likely) Pathogenic APC variants.
Evidence considered
  • The APC InSiGHT VCEP rule allows BP2 supporting for an observation in trans with a (Likely) Pathogenic APC variant or for at least three observations in unknown phase with different (Likely) Pathogenic APC variants.
  • No affected-proband, phase, cis/trans, or qualifying count of pathogenic APC partner-variant observations is documented for NM_000038.6:c.2677G>A (NP_000029.2:p.(Glu893Lys)).
Still missing
  • Documented family or proband-level phase information is needed to establish BP2, including a pathogenic APC variant in trans or at least three unknown-phase observations with different pathogenic variants.
Sources
cspec ↗
BP5 Not assessed: no alternate-gene Pathogenic/Likely pathogenic variant and no documented colorectal-polyposis phenotype are available for the APC VCEP BP5 rule. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits BP5 at Supporting only for an alternate genetic basis of a colorectal polyposis phenotype, specifically a (Likely) Pathogenic variant in another adenomatous-polyposis gene, and only when colorectal polyposis is present. The available case evidence documents no such alternate-gene pathogenic variant and does not establish the required phenotype, so BP5 cannot be assessed.

Rule
APC InSiGHT VCEP BP5 Supporting: only applicable for an alternate genetic basis of the colorectal polyposis phenotype; the instruction specifies a (Likely) Pathogenic variant in another adenomatous-polyposis gene.
Evidence considered
  • The APC InSiGHT VCEP BP5 instruction requires a (Likely) Pathogenic variant in another adenomatous-polyposis gene, including POLD1 or POLE heterozygous variants, MUTYH/NTHL1/MSH3 biallelic variants, or specified childhood/adolescent mismatch-repair-gene biallelic variants; it is only applicable when a colorectal polyposis phenotype is present.
  • The available exact-variant ClinVar submissions concern APC c.2677G>A and contain no documented alternate-gene Pathogenic/Likely pathogenic result or case phenotype sufficient for BP5.
Still missing
  • No documented alternate pathogenic or likely pathogenic variant in an eligible adenomatous-polyposis gene.
  • No documented colorectal-polyposis phenotype for this case.
Sources
cspec ↗clinvar ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: NM_000038.6:c.2677G>A produces p.Glu893Lys, a missense substitution rather than a nonsense, frameshift, or canonical splice loss-of-function variant. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. The governing APC InSiGHT/ClinGen VCEP framework recognizes loss of function as a disease mechanism, but this variant is NM_000038.6:c.2677G>A, an exonic missense substitution producing NP_000029.2:p.(Glu893Lys) in exon 16, not a nonsense, frameshift, or canonical splice-consensus loss-of-function variant. Therefore, no PVS1 strength tier is assigned; the generic SVI PVS1 framework is not applicable to this consequence.

Rule
APC InSiGHT/ClinGen VCEP PVS1 decision tree; missense substitutions are not PVS1 null-variant categories.
Evidence considered
  • The APC InSiGHT/ClinGen VCEP specification identifies APC loss of function as a known disease mechanism and provides an APC-specific PVS1 decision tree.
  • The normalized variant is NM_000038.6:c.2677G>A, encoding NP_000029.2:p.(Glu893Lys), and variant annotation places it in exon 16.
  • The APC-specific PVS1 decision tree applies to listed null or splice-altering variants; this missense substitution is not one of those PVS1 categories.
Sources
cspec ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20pvs1_variant_assessment
PM1 VCEPNot applicable: the APC VCEP explicitly marks PM1 as not applicable, and its authoritative APC domain table contains no entries. Details ▾Hide ▴
Reasoning

The governing APC VCEP specification marks PM1 as not applicable. The case's authoritative vcep_materials.json domain_tables entry for APC is empty, so there is no approved APC critical-domain entry in that authoritative table to which residue 893 can be matched. Generic hotspot or domain reasoning cannot override the gene-specific PM1 restriction.

VCEP rule
APC VCEP PM1: Not Applicable.
Evidence considered
  • The APC VCEP specification marks PM1 as not applicable.
Sources
cspec ↗
PM3 VCEPNot applicable: the APC VCEP excludes PM3 because APC-associated familial adenomatous polyposis is autosomal dominant, not recessive. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification marks PM3 as not applicable because familial adenomatous polyposis due to APC is autosomal dominant rather than a recessive disorder requiring biallelic or trans observations. Therefore, affected-proband observations with a pathogenic variant in trans are not used for PM3 in this framework.

VCEP rule
PM3 is not applicable for APC under the InSiGHT VCEP specification because APC-associated familial adenomatous polyposis is autosomal dominant.
Evidence considered
  • The APC InSiGHT VCEP specification explicitly lists PM3 as not applicable.
  • The governing framework identifies familial adenomatous polyposis 1 due to APC as autosomal dominant, so PM3's recessive-disease logic does not apply.
Sources
cspec ↗
PM4 VCEPNot applicable: the APC VCEP does not use PM4 because data for protein-length changes are limited, and this variant causes no protein-length change. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the governing APC InSiGHT/ClinGen VCEP specification. The APC supplementary specifications explicitly state that PM4 is not used because of limited available data for protein-length changes. This variant is also a missense substitution, p.(Glu893Lys), with no protein-length change.

VCEP rule
APC InSiGHT/ClinGen VCEP specification: PM4 not used due to limited available data for protein-length changes.
Evidence considered
  • The APC VCEP supplementary specifications state that PM4 is not used due to limited available data.
  • The normalized consequence is a missense substitution, NP_000029.2:p.(Glu893Lys), so the protein length is unchanged.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP2 VCEPNot applicable: the APC VCEP explicitly excludes PP2 for APC missense variants. Details ▾Hide ▴
Reasoning

The governing APC VCEP specification marks PP2 as not applicable because APC missense variants are not a sufficiently characteristic disease mechanism for use of this criterion.

VCEP rule
APC VCEP PP2: Not Applicable.
Evidence considered
  • The APC VCEP specification marks PP2 as not applicable for APC.
Sources
cspec ↗
PP4 VCEPNot applicable: the APC VCEP marks PP4 unavailable because phenotype specificity is captured by its PS4 phenotype-point system. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks PP4 as not applicable and states that the phenotype is already captured by its PS4 specifications. Generic PP4 cannot be applied in place of the governing gene-specific framework.

VCEP rule
APC InSiGHT VCEP PP4: Not applicable.
Evidence considered
  • The APC InSiGHT VCEP lists PP4 as Not applicable and notes that the patient's phenotype or family history is already captured by the PS4 specifications.
Sources
cspec ↗
PP5 VCEPNot applicable: the APC VCEP excludes PP5, and this exact variant has no ClinVar expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks PP5 as not applicable and recommends against its use. The exact-variant ClinVar record has zero expert-panel submissions; its classifications are ordinary single-submitter laboratory assertions, including uncertain significance and likely benign, so none can trigger PP5.

VCEP rule
APC InSiGHT VCEP PP5: Not applicable; an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is additionally required by the requested adjudication rule, and none is present.
Evidence considered
  • The APC InSiGHT VCEP states that PP5 is not applicable and is not for use as recommended by the ClinGen SVI VCEP Review Committee.
  • The exact-variant ClinVar audit reports zero expert-panel submissions; available assertions are single-submitter laboratory classifications, with seven uncertain-significance laboratories, two likely-benign laboratories, and one additional uncertain-significance submission.
Sources
cspec ↗clinvar ↗
BP3 VCEPNot applicable: the APC VCEP designates BP3 as not applicable, and p.Glu893Lys is a missense substitution rather than an in-frame length change in a repeat region. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the governing APC InSiGHT/ClinGen VCEP specification, which designates BP3 as not applicable. Independently, this variant is a missense substitution, p.(Glu893Lys), rather than an in-frame deletion or insertion in a repetitive region, so the BP3 evidence model does not fit.

VCEP rule
APC InSiGHT/ClinGen VCEP specification: BP3 not applicable.
Evidence considered
  • The APC VCEP criteria table lists BP3 as not applicable.
  • The normalized variant consequence is missense, NP_000029.2:p.(Glu893Lys), with no in-frame deletion or insertion and no associated protein-length change.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI max delta 0.002. Details ▾Hide ▴
Reasoning

The variant is missense, NM_000038.6:c.2677G>A (p.Glu893Lys). The governing APC VCEP explicitly states that BP4 is not applicable to missense variants; therefore BP4 is not evaluated, and the SpliceAI result is not used to create BP4 support for this missense variant.

Rule
APC VCEP Version 2.1 BP4 Supporting: Missense variants: BP4 is not applicable. Synonymous or intronic variants require multiple in silico splicing predictors suggesting no impact.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The APC Version 2.1 VCEP BP4 rule states: missense variants: BP4 is not applicable.
  • SpliceAI reports a max delta score of 0.002, but it is not evaluated for BP4 because BP4 is upstream not_applicable for this missense variant.
Sources
cspec ↗
BP6 VCEPNot applicable: the APC VCEP excludes BP6, and the exact variant has no ClinVar expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks BP6 as not applicable and recommends against its use. The exact-variant ClinVar record has no expert-panel submission; the two Likely benign classifications are ordinary single-submitter laboratory assertions and therefore cannot trigger BP6 under the requested rule.

VCEP rule
APC InSiGHT VCEP BP6: Not applicable; an exact-variant ClinVar expert-panel Benign or Likely benign classification is additionally required by the requested adjudication rule, and none is present.
Evidence considered
  • The APC InSiGHT VCEP states that BP6 is not applicable and is not for use as recommended by the ClinGen SVI VCEP Review Committee.
  • The exact-variant ClinVar audit reports zero expert-panel submissions; the two Likely benign classifications are single-submitter clinical-laboratory assertions, not expert-panel classifications.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: this is a missense p.Glu893Lys variant, whereas BP7 is restricted to synonymous variants under the APC VCEP rule. Details ▾Hide ▴
Reasoning

The variant is missense, NM_000038.6:c.2677G>A (p.Glu893Lys), not synonymous or intronic. BP7 is restricted to synonymous variants under the requested criterion scope and the APC VCEP rule, so no splice-prediction evidence is evaluated for BP7.

Rule
APC VCEP Version 2.1 BP7 Supporting: 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 or creation of a new splice site.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The APC Version 2.1 VCEP BP7 rule applies to a synonymous or intronic variant at or beyond +7/-21 with multiple splice predictors showing no impact; this missense variant does not meet that scope.
Sources
cspec ↗

Identifiers

Gene
APC
Transcript
NM_000038.6
Coding (HGVS c.)
NM_000038.6:c.2677G>A
Protein (HGVS p.)
NP_000029.2:p.(Glu893Lys)
GRCh38
chr5:112838271 G>A
GRCh37
chr5:112173968 G>A
Location and type
Exon 16 · missense
ClinVar
2562362, 1417738, 1001105, 934037, 927196, 41501
COSMIC
COSV57384932

Gene diagram

Every interpreted variant in APC, mapped onto the exon structure of NM_000038.6. Select a row to find it on the plot.

APCNM_000038.6
Fetching transcript structure from UCSC…
gnomAD v4.1 36 / 1,614,100 alleles AF 2.23e-05 · 0 homozygotes · FAF 1.99e-05
gnomAD v2.1 6 / 250,796 alleles AF 2.39e-05 · 0 homozygotes · FAF 2.3e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.2e-05 · 36 / 1,614,100 alleles · 0 hom · FAF 2e-05
Remaining individuals3 / 62,488 4.8e-05
European (non-Finnish)33 / 1,180,050 2.8e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 2.4e-05 · 6 / 250,796 alleles · 0 hom · FAF 2.3e-05
European (non-Finnish)6 / 113,174 5.3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -188 bp
0.002
SpliceAI acceptor gainat +421 bp
0.000
SpliceAI donor lossat +297 bp
0.000
SpliceAI donor gainat -48 bp
0.001
Pangolin splice lossmagnitude shown
-0.007
Pangolin splice gain
0.005

Other predictors

REVEL
0.617
BayesDel
0.149

How the predictions were used

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. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_000038.6:c.2677G>A (p.Glu893Lys), so the applicable calibrated computational path is REVEL rather than SpliceAI. REVEL is 0.617, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997). The APC VCEP specifies PP3 at Supporting strength and directs that presumed missense variants be evaluated with in silico splicing predictors for possible splicing effects; however, no VCEP lookup or other supporting material directly pre-assigns PP3 for this variant, and the supplied missense-path rule prohibits substituting the SpliceAI result for the below-threshold REVEL score. BayesDel is not used because no applicable APC cutoff is specified and no generic ACMG-strength calibration is established.

Rule
APC VCEP Version 2.1 PP3 Supporting: Missense variants should not use computational prediction models for conservation or evolution; in silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The local REVEL lookup reports a score of 0.617 for GRCh38 chr5:112838271 G>A.
  • The supplied ClinGen SVI REVEL calibration sets supporting PP3 at >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The APC Version 2.1 VCEP specifies PP3 as Supporting and states for missense variants that in silico splicing predictors should be used to reveal possible splicing effects; no variant-specific pre-assigned PP3 code is present in the governing materials.
  • The available BayesDel score is not used because the supplied instructions establish no generic ACMG-strength calibration for BayesDel and the APC VCEP supplies no applicable BayesDel cutoff.
Sources
cspec ↗revel
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for missense variants, regardless of the available SpliceAI max delta 0.002. Details ▾Hide ▴
Reasoning

The variant is missense, NM_000038.6:c.2677G>A (p.Glu893Lys). The governing APC VCEP explicitly states that BP4 is not applicable to missense variants; therefore BP4 is not evaluated, and the SpliceAI result is not used to create BP4 support for this missense variant.

Rule
APC VCEP Version 2.1 BP4 Supporting: Missense variants: BP4 is not applicable. Synonymous or intronic variants require multiple in silico splicing predictors suggesting no impact.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The APC Version 2.1 VCEP BP4 rule states: missense variants: BP4 is not applicable.
  • SpliceAI reports a max delta score of 0.002, but it is not evaluated for BP4 because BP4 is upstream not_applicable for this missense variant.
Sources
cspec ↗
BP7 N/ANot applicable: this is a missense p.Glu893Lys variant, whereas BP7 is restricted to synonymous variants under the APC VCEP rule. Details ▾Hide ▴
Reasoning

The variant is missense, NM_000038.6:c.2677G>A (p.Glu893Lys), not synonymous or intronic. BP7 is restricted to synonymous variants under the requested criterion scope and the APC VCEP rule, so no splice-prediction evidence is evaluated for BP7.

Rule
APC VCEP Version 2.1 BP7 Supporting: 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 or creation of a new splice site.
Evidence considered
  • VariantValidator normalizes NM_000038.6:c.2677G>A to the missense consequence NP_000029.2:p.(Glu893Lys).
  • The APC Version 2.1 VCEP BP7 rule applies to a synonymous or intronic variant at or beyond +7/-21 with multiple splice predictors showing no impact; this missense variant does not meet that scope.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.617. BayesDel score = 0.149074.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    This source gives general hereditary-cancer phenotype context for APC-associated familial adenomatous polyposis, including adenomatous polyposis and extracolonic manifestations, but does not mention APC c.2677G>A or p.(E893K) and does not provide variant-specific prevalence evidence.
    Does not name this variant
    PMID 15604628 ↗
    Quoted passage
    Familial adenomatous polyposis (FAP); Attenuated FAP; ... Adenomatous polyposis, colorectal cancer, papillary thyroid cancer, gastric cancer, periampullary carcinoma, adrenal cancer, hepatoblastoma and extracolonic manifestations.

    Table I, Selected Hereditary Syndromes Associated With an Increased Risk of Common Cancers

  • Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.
    Johnston JJ et al. · 2012
    The paper does not mention APC c.2677G>A or p.(E893K). It reports aggregate APC variant counts from an exome-sequencing study but provides no variant-specific functional, segregation, de novo, affected-relative, or non-segregation data for this variant.
    Does not name this variant
    PMID 22703879 ↗
    Quoted passage
    APC NG_008481.4 familial adenomatous polyposis 175100, 611731, and 135290 45 1 6 – 38 – –

    Table 1, APC row

  • 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.
    Hampel H et al. · 2015
    This practice guideline describes FAP referral features, including cumulative adenomatous colon polyps and selected extracolonic findings, but does not report APC c.2677G>A or p.(E893K) and provides no variant-specific case-control or phenotype-point evidence.
    Does not name this variant
    PMID 25394175 ↗
    Quoted passage
    >= 10 cumulative adenomatous colon polyps in the same person

    Table 1, Colorectal polyposis, adenomatous

  • 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.
    Stoffel EM et al. · 2015
    No paper-specific finding is recorded.
    PMID 25452455 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint co
    This ACMG/AMP guidance paper does not study APC c.2677G>A or p.(Glu893Lys); it states that functional studies are informative when biologically relevant, validated, reproducible, and robust, but supplies no assay result for this variant.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    The impact of a missense change depends on criteria such as the evolutionary conservation of an amino acid or nucleotide, the location and context within the protein sequence, and the biochemical consequence of the amino acid substitution.

    Computational (In Silico) Predictive Programs; Proposed Criteria for Interpretation of Sequence Variants, PS3/BS3 Functional studies

  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi
    No paper-specific finding is recorded.
    PMID 26389258 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite
    No paper-specific finding is recorded.
    PMID 28492532 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and geno
    No paper-specific finding is recorded.
    PMID 34012068 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 36 / 1,614,100 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.002 Open source ↗
ClinVar 7 Uncertain significance · 2 Likely benign · 1 Uncertain Significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.617. BayesDel score = 0.149074.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57384932, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.