0%
APCc.6196A>GLikely benign
Print report
Variant interpretation report

APC c.6196A>G, p.(Arg2066Gly)

NM_001127510.3:c.6196A>G NP_001120982.1:p.(Arg2066Gly) Missense · exon 17 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

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: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BS1Strong
BS1 · strong

Met, strong: gnomAD v4.1 Popmax Filtering AF 2.314e-05 exceeds the APC VCEP BS1 threshold of 1e-05.

BP1Supporting
BP1 · supporting

Met at supporting: APC codon 2066 is outside the VCEP BP1 exception limited to the first beta-catenin-binding repeat, codons 1021-1035.

Recorded classification: Likely benign

Likely Benign: BS1 strong plus BP1 supporting satisfy Rule26 of the APC InSiGHT VCEP Version 2.1 framework.

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
38 / 1,613,984 alleles

gnomAD v4.1: 38 / 1,613,984 alleles. Recorded AF 2.35442e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.08903e-06; MAF= 0.00071%, 2/282126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55598e-05; MAF= 0.00156%, 2/128536 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.572 recorded score

Recorded REVEL score: 0.572. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
10 reported laboratory submissions

9 Uncertain significance · 1 Uncertain Significance.

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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV104567844, n = 1 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: 2 met · 5 not met · 10 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 ClinGen InSiGHT APC VCEP Version 2.1 framework governs PS2, PM6, PP1, and BS4.

The available variant-specific publication reports one R2066G carrier but no parental testing, segregation, informative meioses, or affected non-carrier relatives; none of the four requested criteria can be assigned.

Met · 2

BS1 StrongMet, strong: gnomAD v4.1 Popmax Filtering AF 2.314e-05 exceeds the APC VCEP BS1 threshold of 1e-05. Details ▾Hide ▴
Reasoning

The APC VCEP BS1 rule requires a gnomAD Popmax Filtering Allele Frequency of at least 0.00001 (0.001%). gnomAD v4.1 reports a grpmax FAF of 0.00002314 (2.314e-05), exceeding this threshold; its highest observed subpopulation AF is 3.1357e-05. The result is based on the governing VCEP threshold and the all-comers default population source because the APC specification does not require a non-cancer or exome-only source. Therefore, BS1 is met at strong strength.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001).
Evidence considered
  • The APC VCEP specifies BS1 at gnomAD Popmax Filtering AF >= 0.001% (0.00001), at strong strength.
  • gnomAD v4.1 reports grpmax FAF 2.314e-05 and highest observed subpopulation AF 3.135704830171922e-05, both above 1e-05.
  • The APC specification does not identify a required non-cancer or exome-only population source, so the all-comers gnomAD v4.1 entry is the applicable default.
Sources
cspec ↗gnomad_v4 ↗
BP1 SupportingMet at supporting: APC codon 2066 is outside the VCEP BP1 exception limited to the first beta-catenin-binding repeat, codons 1021-1035. Details ▾Hide ▴
Reasoning

The APC VCEP version 2.1 applies BP1 to APC missense variants except those located in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035. The assessed missense variant is p.Arg2066Gly at codon 2066, outside that explicit exception, so BP1_Supporting applies.

Rule
APC VCEP BP1_Supporting: applicable to APC missense variants except missense variants in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.
Evidence considered
  • The APC VCEP version 2.1 states that BP1 is applicable to APC missense variants except variants in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.
  • The assessed variant is missense p.Arg2066Gly at codon 2066, which is outside codons 1021-1035.
Sources
cspec ↗

Not met · 5 · evaluated, threshold not reached

PS1 Not met: p.Arg2066Gly matches neither of the APC VCEP's two established likely pathogenic missense changes, p.Asn1026Ser or p.Ser1028Arg. Details ▾Hide ▴
Reasoning

The APC VCEP version 2.1 specifies PS1 for a missense variant only when it produces the same amino-acid change as a previously established pathogenic or likely pathogenic APC variant. The target is p.Arg2066Gly, whereas the VCEP identifies only p.Asn1026Ser and p.Ser1028Arg as the currently established likely pathogenic APC missense variants; no pathogenic or likely pathogenic variant producing p.Arg2066Gly was identified.

Rule
APC VCEP PS1: same amino-acid change as a previously established pathogenic or likely pathogenic missense variant; the VCEP lists only p.Asn1026Ser and p.Ser1028Arg as established likely pathogenic APC missense variants.
Evidence considered
  • The APC VCEP version 2.1 requires the same amino-acid change for missense PS1 and lists only p.Asn1026Ser and p.Ser1028Arg as established likely pathogenic APC missense variants.
  • The assessed variant is NM_001127510.3:c.6196A>G, p.Arg2066Gly; no established pathogenic or likely pathogenic same-amino-acid comparator was identified in the available evidence.
Sources
cspec ↗
PM2 Not met: gnomAD v4.1 AF 2.35442e-05 with AC 38 exceeds the APC VCEP PM2 threshold of 3e-06 for AC greater than 1. Details ▾Hide ▴
Reasoning

The APC VCEP PM2 rule defines rare in controls as allele frequency <=0.000003 (0.0003%) when allele count is greater than 1, or allele frequency <0.00001 (0.001%) when allele count is 1 or less. Using the applicable all-comers default because the APC specification does not require a non-cancer or exome-only source, gnomAD v4.1 shows AC 38 and AF 2.35442e-05, above the AC>1 threshold; gnomAD v2.1 shows AC 2 and AF 7.08903e-06, also above 0.000003. Thus PM2 is not met. The available non-cancer subsets do not change this adjudication because they are not the source specified by the governing VCEP.

Rule
Rare in controls: AF <= 0.0003% (0.000003) if allele count is > 1, or AF < 0.001% (0.00001) if allele count is <= 1.
Evidence considered
  • The APC VCEP defines PM2 Supporting as AF <= 0.000003 when allele count is >1, or AF <0.00001 when allele count is <=1.
  • gnomAD v4.1 reports total AC 38 and total AF 2.3544223486726016e-05, exceeding the applicable AC>1 threshold.
  • gnomAD v2.1 reports total AC 2 and total AF 7.089031142113807e-06, also exceeding the applicable AC>1 threshold.
  • The APC VCEP rule does not specify a non-cancer or exome-only source, so all-comers gnomAD entries are used rather than the available non-cancer subsets.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
PM5 Not met: no pathogenic or likely pathogenic alternate missense variant at APC residue Arg2066 was identified for comparison with p.Arg2066Gly. Details ▾Hide ▴
Reasoning

The APC VCEP version 2.1 permits PM5 for a missense variant at a residue with a different missense change that is established pathogenic or likely pathogenic under APC-specific modifications, with the assessed substitution meeting the required Grantham-distance comparison. The target is p.Arg2066Gly, but no same-residue comparator at Arg2066 was identified, and the available report of R2066G only lists the target variant without a pathogenic or likely pathogenic alternate at that residue.

Rule
APC VCEP PM5: a different missense variant at the same residue established as pathogenic or likely pathogenic under APC-specific modifications, with the assessed variant's Grantham distance equal to or greater than that of the reported variant.
Evidence considered
  • The APC VCEP version 2.1 requires a different missense change at the same amino-acid residue that is established pathogenic or likely pathogenic under APC-specific modifications, with an adequate Grantham-distance comparison.
  • The PM5 candidate collection found seven candidates overall but zero same-residue candidates, zero expert-panel or non-expert-majority pathogenic/likely pathogenic same-residue candidates, and zero conflicted same-residue candidates.
  • The Azzopardi et al. report lists R2066G in one non-FAP, non-MUTYH-associated polyposis patient but does not report a pathogenic or likely pathogenic alternate missense variant at Arg2066.
Sources
cspec ↗pm5_candidatesPMID:18199528 ↗
BA1 Not met: gnomAD v4.1 Popmax Filtering AF 2.314e-05 is below the APC VCEP BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The APC VCEP BA1 rule requires a gnomAD Popmax Filtering Allele Frequency of at least 0.001 (0.1%). The available all-comers gnomAD v4.1 grpmax FAF is 0.00002314 (2.314e-05), and the highest observed subpopulation AF is 0.000031357 (3.1357e-05), both far below 0.001. The gnomAD v2.1 all-comers AF is also only 7.08903e-06. Therefore, BA1 is not met.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001).
Evidence considered
  • The APC VCEP specifies BA1 at gnomAD Popmax Filtering AF >= 0.001 (0.1%).
  • gnomAD v4.1 reports grpmax FAF 2.314e-05, with highest observed subpopulation AF 3.135704830171922e-05.
  • gnomAD v2.1 reports all-comers AF 7.089031142113807e-06; neither dataset approaches the BA1 threshold.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BP2 Not met: R2066G was reported in one patient, but no pathogenic APC partner or cis/trans phase was documented, so the VCEP threshold was not satisfied. Details ▾Hide ▴
Reasoning

The APC VCEP Version 2.1 permits BP2 at Supporting strength when the variant is observed in trans with a (Likely) Pathogenic APC variant or at least three times in unknown phase with different (Likely) Pathogenic APC variants. PMID:18199528 reports APC R2066G in one non-FAP, non-MAP patient with multiple colorectal adenomas, but does not report a second pathogenic APC variant, cis/trans phase, or three qualifying observations. Thus the BP2 threshold is not met.

Rule
Observed in trans with a (Likely) Pathogenic APC variant OR at least 3 times in an unknown phase with different (Likely) Pathogenic APC variants.
Evidence considered
  • The APC VCEP Version 2.1 defines BP2 as Supporting only for observation in trans with a (Likely) Pathogenic APC variant or at least three observations in unknown phase with different (Likely) Pathogenic APC variants.
  • Azzopardi et al. report R2066G in one non-FAP, non-MAP patient with multiple colorectal adenomas; the paper does not report a pathogenic APC partner, cis/trans phase, or three qualifying observations.
  • The paper's Table 1 lists R2066G among variants identified in the multiple-CRA subgroup, with 35 of 201 patients carrying variants overall; this is not evidence of the phase or pathogenic-partner requirement for BP2.
Still missing
  • No documented pathogenic or likely pathogenic APC variant in the same individual was available for phase assessment.
  • No evidence of at least three independent observations with different pathogenic or likely pathogenic APC variants in unknown phase was available.
Sources
cspec ↗PMID:18199528 ↗

Not assessed · 10 · no assessment recorded

PS2 Not assessed: no de novo score, parental genotypes, or confirmed maternity and paternity are documented for APC c.6196A>G. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PS2 from de novo scores, with Moderate requiring 1-1.5 scores, Strong requiring 2-3.5 scores, and Very Strong requiring at least 4 scores. The available case evidence does not document a de novo observation, confirmed maternity and paternity, parental genotypes, or a phenotype-point-based de novo score for APC c.6196A>G (p.Arg2066Gly). PMID:18199528 identifies R2066G in one patient but explicitly provides no variant-specific segregation or parental-testing result, so PS2 cannot be applied.

Rule
APC VCEP PS2: Very Strong for >=4 de novo scores; Strong for 2-3.5 de novo scores; Moderate for 1-1.5 de novo scores. De novo scores are curated using VCEP Tables 1 and 2.
Evidence considered
  • The APC VCEP PS2 rule assigns 1-1.5 de novo scores to PS2_Moderate, 2-3.5 to PS2_Strong, and at least 4 to PS2_Very Strong.
  • The APC VCEP Table 1/2 framework derives de novo scores from phenotype points and whether parental relationships are confirmed; those case-level inputs are not reported.
  • PMID:18199528 reports R2066G in one non-FAP, non-MUTYH-associated polyposis patient but states that variant-specific segregation results were not reported.
Still missing
  • Documented de novo status for the proband
  • Parental genotypes with confirmed maternity and paternity
  • APC VCEP phenotype-point assessment for the proband
Sources
cspec ↗vcep_table_1_262PMID:18199528 ↗
PS3 Not assessed: the exact-variant report tested other APC variants, with no validated damaging assay result reported for p.Arg2066Gly. Details ▾Hide ▴
Reasoning

The APC ClinGen InSiGHT VCEP specification calibrates PS3 to defined RNA assay findings or protein evidence of increased beta-catenin-regulated transcription and/or decreased beta-catenin binding for variants in the beta-catenin binding domain. This missense variant encodes p.Arg2066Gly, within the specified codon 959-2129 region, but the exact-variant literature report only lists R2066G among variants identified in a non-FAP/non-MAP polyposis cohort and states that functional assays tested other nonsynonymous variants, not R2066G. No validated assay demonstrating a damaging effect for p.Arg2066Gly, with adequate controls and quantitative calibration, was identified; therefore PS3 cannot be applied.

Rule
APC VCEP PS3: RNA assays show a premature stop codon or specified exon skipping/loss at the calibrated strength, or protein assays show increased beta-catenin regulated transcription activity and/or decreased binding to beta-catenin by surface plasmon resonance for variants within the beta-catenin binding domain (codons 959-2129).
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification defines PS3 for RNA assay evidence of premature termination or specified exon skipping/loss, and for protein assays showing increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding within codons 959-2129.
  • PMID:18199528 reports APC R2066G in one non-FAP/non-MAP polyposis patient but explicitly indicates that functional assays evaluated 16 other nonsynonymous variants rather than R2066G.
Still missing
  • A validated RNA or protein functional assay for APC p.Arg2066Gly with appropriate controls and quantitative results is needed.
Sources
cspec ↗PMID:18199528 ↗
PS4 Not assessed: APC R2066G was reported in one patient, but the adenoma count needed for the VCEP phenotype-point thresholds is unspecified. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PS4 by phenotype points: >= 16 points for Very Strong, 4-15.5 for Strong, 2-3.5 for Moderate, and 1-1.5 for Supporting, with phenotype curation defined in Table 1. PMID:18199528 reports APC R2066G in one patient from a non-FAP, non-MUTYH-associated multiple-colorectal-adenoma subgroup, but the number and phenotype details of that patient's adenomas are not specified. Therefore no VCEP phenotype point can be assigned and PS4 cannot be assessed from the available evidence.

Rule
>= 16 phenotype points = Very Strong; 4-15.5 phenotype points = Strong; 2-3.5 phenotype points = Moderate; 1-1.5 phenotype point = Supporting. For phenotype points curation see Table 1.
Evidence considered
  • The APC InSiGHT VCEP rule states: >= 16 phenotype points for PS4 Very Strong, 4-15.5 phenotype points for Strong, 2-3.5 phenotype points for Moderate, and 1-1.5 phenotype point for Supporting; phenotype-point curation is specified in Table 1.
  • PMID:18199528 explicitly lists R2066G in one patient in the non-FAP, non-MAP multiple-colorectal-adenoma subgroup, but does not specify that patient's adenoma count or sufficient additional phenotype detail for VCEP point assignment.
Still missing
  • Obtain the individual patient's phenotype details, especially the cumulative colorectal adenoma count and other APC-specific phenotype features, to assign VCEP phenotype points.
Sources
cspec ↗vcep_table_1_262PMID:18199528 ↗
PM6 Not assessed: the only variant-specific report describes R2066G as inherited but provides no parental results or VCEP de novo score. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PM6 from assumed de novo scores without confirmed parental relationships: Supporting for 0.5, Moderate for 1-1.5, and Strong for 2-3.5 de novo scores. No report in the available evidence states that APC c.6196A>G (p.Arg2066Gly) was assumed de novo, gives parental-testing results, or provides the phenotype points needed to calculate a PM6 score. PMID:18199528 describes the variant as inherited in a patient but supplies no parental or segregation analysis; therefore PM6 is not applied.

Rule
APC VCEP PM6: Strong for 2-3.5 de novo scores; Moderate for 1-1.5 de novo scores; Supporting for 0.5 de novo scores. De novo scores are curated using VCEP Tables 1 and 2.
Evidence considered
  • The APC VCEP PM6 rule assigns 0.5 de novo scores to PM6_Supporting, 1-1.5 to PM6_Moderate, and 2-3.5 to PM6_Strong.
  • PMID:18199528 identifies R2066G as a rare inherited nonsynonymous variant in one patient and reports no variant-specific parental or segregation result.
  • Because an assumed de novo observation and its phenotype-based score are not documented, PM6 cannot be assigned even at Supporting strength.
Still missing
  • Clarification of whether the proband's variant was assumed de novo
  • Parental genotypes or documented absence of parental testing
  • APC VCEP phenotype-point assessment
Sources
cspec ↗vcep_table_1_262PMID:18199528 ↗
PP1 Not assessed: no informative meioses, affected relatives, or family-level segregation data are reported for APC c.6196A>G. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PP1 Supporting for segregation through 3-4 meioses in at least one family, Moderate for 5-6 meioses in at least one family, and Strong for at least 7 meioses in at least 2 families. The available evidence contains no affected relatives, family structure, informative meioses, co-segregating genotypes, or segregation results for APC c.6196A>G (p.Arg2066Gly). PMID:18199528 reports one variant-bearing patient without variant-specific segregation analysis, so PP1 is not assessable.

Rule
APC VCEP PP1: Strong for segregation in >=7 meioses in >=2 families; Moderate for 5-6 meioses in >=1 family; Supporting for 3-4 meioses in >=1 family.
Evidence considered
  • The APC VCEP PP1 rule requires 3-4 segregating meioses for Supporting, 5-6 for Moderate, and at least 7 meioses in at least 2 families for Strong.
  • PMID:18199528 reports R2066G in one patient but does not report variant-specific segregation results.
  • No family pedigree, affected-relative genotype, or informative-meiosis count is available for this variant.
Still missing
  • Family pedigrees and affected-relative phenotypes
  • Genotypes of informative relatives
  • Count of informative meioses and number of families
Sources
cspec ↗PMID:18199528 ↗
PP3 Not assessed: SpliceAI returned no score, while REVEL 0.572 is below the generic PP3 supporting threshold of 0.644. Details ▾Hide ▴
Reasoning

PP3 is applicable because NM_001127510.3:c.6196A>G is a missense variant, p.(Arg2066Gly). The APC VCEP specifies PP3 at Supporting strength when multiple in silico splicing predictors support a deleterious effect, including use of in silico splicing predictors for presumed missense variants to identify possible splicing effects. SpliceAI returned no score, which is missing data and cannot be treated as a zero or as evidence against splice impact. The available Pangolin scores are not calibrated for PP3/BP4 in this assessment. REVEL is 0.572, below the generic PP3 Supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), and BayesDel has no generic ACMG strength calibration; neither therefore establishes PP3 under the governing APC specification. The criterion cannot be assessed definitively without an applicable calibrated splice-prediction result or other governing-VCEP-supported computational evidence.

Rule
APC VCEP Version 2.1: PP3 Supporting—missense variants should use in silico splicing predictors to reveal possible splicing effects; non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • The variant is missense: NM_001127510.3:c.6196A>G, NP_001120982.1:p.(Arg2066Gly), so PP3 is within scope.
  • The APC VCEP Version 2.1 PP3 rule states that presumed missense variants should be evaluated with in silico splicing predictors and that multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
  • SpliceAI returned no scores and max delta is null; this is missing data, not a score of 0 and not evidence of absent splice impact.
  • Pangolin scores are present (SG 0.025 and SL -0.001), but Pangolin is not calibrated for PP3/BP4 in this assessment.
  • REVEL score 0.572 is below the generic PP3 Supporting threshold of 0.644 from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
  • BayesDel score 0.333397 is not usable for PP3 strength because no generic ACMG/AMP calibration is established and the APC VCEP does not specify a BayesDel cutoff.
Still missing
  • No SpliceAI score is available for this variant.
  • No multiple calibrated in silico splicing-predictor result supporting a deleterious effect is available.
Sources
cspec ↗spliceai ↗revelbayesdel
BS2 Not assessed: gnomAD v4.1 reports 0 homozygotes, but no qualifying healthy-individual data are available to evaluate the alternative 10-point BS2 branch. Details ▾Hide ▴
Reasoning

The APC VCEP BS2 rule requires either at least 10 points from defined healthy individuals or at least 2 observations in the homozygous state. gnomAD v2.1 and v4.1 report zero homozygotes, so the homozygote branch is not met. However, the available population data do not provide the age, colonoscopy, indication-for-testing, or phenotype details required to calculate APC healthy-individual points. The evidence is therefore insufficient to assess the complete BS2 criterion.

Rule
>= 10 points for healthy individuals OR >= 2 times in homozygous state for strong BS2; >= 3 healthy-individual points for supporting BS2.
Evidence considered
  • The APC VCEP specifies BS2 strong at >=10 healthy-individual points or >=2 homozygous observations, with supporting at >=3 healthy-individual points.
  • gnomAD v4.1 reports total_hom 0 and gnomAD v2.1 reports total_hom 0.
  • The gnomAD records do not provide the individual-level clinical details needed to assign APC VCEP healthy-individual points.
Still missing
  • Qualifying APC healthy-individual observations with age, colonoscopy/polyp burden, testing indication, and relevant phenotype details are unavailable.
  • A complete BS2 assessment requires calculation of the APC VCEP healthy-individual points or qualifying homozygous observations.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS3 Not assessed: no exact-variant assay showed wild-type-like APC function or normal splicing for p.Arg2066Gly under the VCEP BS3 requirements. Details ▾Hide ▴
Reasoning

The APC ClinGen InSiGHT VCEP specification permits BS3 supporting for a protein assay showing retention of beta-catenin-regulated transcription activity comparable to wild-type for variants within codons 959-2129, and BS3 strong only for a qualifying RNA assay in a constitutional sample with demonstrated biallelic expression and/or nonsense-mediated decay inhibition. Although p.Arg2066Gly lies within the relevant protein domain, no exact-variant assay showing retained function, normal splicing, or appropriate RNA controls was identified; the available exact-variant report tested other variants. Therefore BS3 cannot be applied.

Rule
APC VCEP BS3: Strong requires an RNA assay of a synonymous or intronic variant in a constitutional patient sample showing no mRNA aberration plus biallelic expression and/or nonsense-mediated decay inhibition; Supporting permits such an RNA result without those controls or a protein assay showing beta-catenin-regulated transcription activity comparable to wild-type for variants within codons 959-2129.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification defines BS3 supporting as retention of beta-catenin-regulated transcription activity comparable to wild-type in a protein assay for variants within codons 959-2129; BS3 strong requires a qualifying constitutional RNA assay with biallelic expression and/or nonsense-mediated decay inhibition.
  • PMID:18199528 lists R2066G as an identified variant but reports functional testing of other nonsynonymous variants, not R2066G, so it provides neither benign functional evidence nor a calibrated assay result for this variant.
Still missing
  • A validated p.Arg2066Gly protein assay showing wild-type-like beta-catenin-regulated transcription or a qualifying controlled RNA assay is needed.
Sources
cspec ↗PMID:18199528 ↗
BS4 Not assessed: no affected non-carrier relative or phenotype-point score is documented for APC c.6196A>G. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS4 Strong when an affected member without the variant has at least 1 phenotype point or at least two such affected members each have at least 0.5 phenotype points, and Supporting when one affected member without the variant has at least 0.5 phenotype points. No affected non-carrier relative, phenotype-point assessment, non-segregation observation, or family genotype data are documented for APC c.6196A>G (p.Arg2066Gly). BS4 therefore cannot be applied.

Rule
APC VCEP BS4: Strong for an affected member without the variant scoring at least 1 phenotype point, or at least two affected members without the variant each scoring at least 0.5 points; Supporting for one affected member without the variant scoring at least 0.5 points.
Evidence considered
  • The APC VCEP BS4 rule requires one affected non-carrier with at least 1 phenotype point, or two affected non-carriers each with at least 0.5 phenotype points, for Strong; one affected non-carrier with at least 0.5 point supports Supporting.
  • No affected non-carrier relative, family genotype, or phenotype-point score is reported in the available case evidence.
Still missing
  • Affected relatives who lack the variant
  • Phenotype-point scoring for those relatives
  • Genotype and phenotype information sufficient to establish non-segregation
Sources
cspec ↗vcep_table_1_262
BP5 Not assessed: multiple colorectal adenomas are reported, but no pathogenic alternate-gene result is documented to satisfy the APC BP5 rule. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP defines BP5 as Supporting only when a colorectal polyposis phenotype is present and a (Likely) Pathogenic variant is identified in another adenomatous-polyposis gene, including POLD1, POLE, MUTYH, NTHL1, MSH3, or specified mismatch-repair genes. The available report documents R2066G in a patient with multiple colorectal adenomas and describes the subgroup as non-FAP/non-MUTYH-associated, but it does not document a pathogenic alternate-gene result in that patient. BP5 therefore cannot be assessed without an alternate molecular diagnosis.

Rule
Supporting: (Likely) Pathogenic variant in another adenomatous polyposis gene; only applicable when a colorectal polyposis phenotype is present.
Evidence considered
  • The APC InSiGHT VCEP BP5 instruction requires a (Likely) Pathogenic variant in another adenomatous-polyposis gene and states that the rule is only applicable when a colorectal polyposis phenotype is present.
  • PMID:18199528 reports R2066G in the non-FAP, non-MAP multiple-colorectal-adenoma subgroup and does not provide an alternate-gene pathogenic finding for the individual.
Still missing
  • Verify whether the patient had a Pathogenic or Likely pathogenic variant in another adenomatous-polyposis gene and document the gene, variant, zygosity, and classification.
Sources
cspec ↗PMID:18199528 ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: NM_001127510.3:c.6196A>G is a missense variant encoding p.(Arg2066Gly), not a null variant eligible for PVS1. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP framework establishes PVS1 for null variants according to its APC-specific PVS1 decision tree. NM_001127510.3:c.6196A>G is a missense substitution encoding NP_001120982.1:p.(Arg2066Gly), not a nonsense, frameshift, or canonical splice-site null variant. Therefore PVS1 is not applicable; no PVS1 strength tier is assigned.

Rule
APC InSiGHT VCEP Version 2.1 PVS1 decision tree: missense variants do not enter the APC null-variant PVS1 categories.
Evidence considered
  • The APC InSiGHT VCEP Version 2.1 specifies PVS1 under the APC-specific decision tree for null variants in a gene where loss of function is a known disease mechanism.
  • The normalized consequence is missense: NM_001127510.3:c.6196A>G, NP_001120982.1:p.(Arg2066Gly).
Sources
cspec ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PM1 VCEPNot applicable: the APC VCEP version 2.1 explicitly designates PM1 as not applicable, and no authoritative APC domain table is supplied. Details ▾Hide ▴
Reasoning

The governing APC VCEP version 2.1 designates PM1 as not applicable. The case's vcep_materials.json contains no domain_tables entry for APC, so there is no authoritative domain-table exception or approved critical-domain list to apply; PM1 is therefore not assigned from general domain or hotspot observations.

VCEP rule
APC VCEP PM1: not applicable.
Evidence considered
  • The APC VCEP version 2.1 marks PM1 as not applicable.
  • The vcep_materials.json domain_tables object is empty for APC; consequently, no approved APC critical functional domain entry is available for residue 2066.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PM3 VCEPNot applicable: APC familial adenomatous polyposis is autosomal dominant, and the APC VCEP explicitly designates PM3 as not applicable. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT APC VCEP Version 2.1 specifies PM3 as not applicable because familial adenomatous polyposis due to APC is an autosomal dominant disorder; therefore recessive in-trans evidence is not used for this variant.

VCEP rule
PM3 is not applicable for APC under the ClinGen InSiGHT VCEP specification because familial adenomatous polyposis is autosomal dominant.
Evidence considered
  • The APC VCEP Version 2.1 lists PM3 as Not Applicable and states that PM3 is not used because familial adenomatous polyposis has autosomal dominant inheritance.
Sources
cspec ↗
PM4 VCEPNot applicable: the APC VCEP does not use PM4, and this variant changes one amino acid without altering protein length. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP supplementary specifications explicitly state that PM4 is not used because of limited available data. Independently, this variant is a missense substitution, p.(Arg2066Gly), and does not produce a protein length change from an in-frame deletion, insertion, or indel. PM4 is therefore not applicable.

VCEP rule
APC InSiGHT VCEP supplementary specification: PM4 is not used due to limited available data; the variant also lacks a protein-length change.
Evidence considered
  • The APC VCEP supplementary material marks PM4 as not used due to limited available data.
  • The variant is a missense substitution encoding p.(Arg2066Gly), with no in-frame deletion, insertion, or other protein-length change.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP2 VCEPNot applicable: the APC VCEP version 2.1 designates PP2 as not applicable for APC missense variants. Details ▾Hide ▴
Reasoning

The governing APC VCEP version 2.1 designates PP2 as not applicable because missense variants are not a frequent disease mechanism for APC-related disease under this specification.

VCEP rule
APC VCEP PP2: not applicable.
Evidence considered
  • The APC VCEP version 2.1 marks PP2 as not applicable rather than permitting generic gene-level missense-enrichment evidence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP4 VCEPNot applicable: the APC VCEP directs that phenotype specificity be captured through PS4 rather than independent PP4 use. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks PP4 as Not Applicable because phenotype specificity is already captured by its PS4 phenotype-point specifications. PP4 is therefore not used independently for this APC variant.

VCEP rule
Not Applicable for APC under the InSiGHT VCEP; phenotype specificity is captured by PS4.
Evidence considered
  • The APC InSiGHT VCEP lists PP4 as Not Applicable and states that the patient's phenotype or family history is already captured by the PS4 specifications.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP5 VCEPNot applicable: APC VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks PP5 as Not Applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact-variant ClinVar record is Uncertain significance with criteria-provided single-submitter status and zero expert-panel submissions, so it does not meet the required exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic condition.

VCEP rule
Not Applicable for APC under the InSiGHT VCEP; PP5 is not for use.
Evidence considered
  • The APC InSiGHT VCEP rule states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar reports this exact variant as Uncertain significance with criteria provided by a single submitter; the case audit reports zero expert-panel submissions.
Sources
cspec ↗clinvar ↗
BP3 VCEPNot applicable: the APC VCEP explicitly marks BP3 as not applicable, and c.6196A>G is not an in-frame indel in a repeat region. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP Version 2.1 explicitly marks BP3 as not applicable. The variant is a missense substitution, NM_001127510.3:c.6196A>G (p.(Arg2066Gly)), rather than an in-frame deletion or insertion in a repetitive region. BP3 is not applicable.

VCEP rule
APC InSiGHT VCEP Version 2.1: BP3 is not applicable.
Evidence considered
  • The APC VCEP criterion table explicitly lists BP3 as not applicable.
  • The normalized variant consequence is missense, p.(Arg2066Gly), not an in-frame indel affecting a repetitive protein region.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
BP4 N/ANot applicable: APC VCEP excludes missense variants from BP4, which is limited to synonymous or intronic splice-impact assessment. Details ▾Hide ▴
Reasoning

BP4 is not applicable because the variant is missense, p.(Arg2066Gly). The governing APC VCEP explicitly states that BP4 is not applicable to missense variants; its BP4 rule is limited to synonymous or intronic variants with multiple in silico splicing predictors suggesting no impact. Per scope, predictor scores were not evaluated for BP4.

Rule
APC VCEP Version 2.1: BP4 is not applicable for missense variants; synonymous or intronic variants require multiple in silico splicing predictors suggesting no impact.
Evidence considered
  • The variant consequence is missense, NP_001120982.1:p.(Arg2066Gly).
  • The APC VCEP Version 2.1 BP4 rule explicitly states: missense variants—BP4 is not applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: APC VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks BP6 as Not Applicable and states that the criterion is not for use. Independently, the exact-variant ClinVar record is Uncertain significance with zero expert-panel submissions, so there is no exact-variant ClinVar expert-panel Benign/Likely benign classification that could satisfy the required BP6 trigger.

VCEP rule
Not Applicable for APC under the InSiGHT VCEP; BP6 is not for use.
Evidence considered
  • The APC InSiGHT VCEP rule states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar reports this exact variant as Uncertain significance with criteria provided by a single submitter; the case audit reports zero expert-panel submissions.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or intronic variants, whereas this variant causes the missense change p.(Arg2066Gly). Details ▾Hide ▴
Reasoning

BP7 is not applicable because the variant is missense, p.(Arg2066Gly), rather than synonymous or intronic. The APC VCEP limits BP7 to synonymous or intronic variants at or beyond +7/-21 with multiple splicing algorithms predicting no splice impact. Per scope, splicing predictors were not evaluated for this out-of-scope criterion.

Rule
APC VCEP Version 2.1: BP7 Supporting applies only to synonymous or intronic variants at or beyond +7/-21 with multiple splicing prediction algorithms predicting no impact.
Evidence considered
  • The variant consequence is missense, NP_001120982.1:p.(Arg2066Gly), not synonymous or intronic.
  • The APC VCEP Version 2.1 BP7 rule applies to synonymous or intronic variants at or beyond +7/-21 with multiple splicing algorithms predicting no impact.
Sources
cspec ↗

Identifiers

Gene
APC
Transcript
NM_001127510.3
Coding (HGVS c.)
NM_001127510.3:c.6196A>G
Protein (HGVS p.)
NP_001120982.1:p.(Arg2066Gly)
GRCh38
chr5:112841790 A>G
GRCh37
chr5:112177487 A>G
Location and type
Exon 17 · missense
ClinVar
826494, 570568, 188063
COSMIC
COSV104567844

Gene diagram

Every interpreted variant in APC, mapped onto the exon structure of NM_001127510.3. Select a row to find it on the plot.

APCNM_001127510.3
Fetching transcript structure from UCSC…
gnomAD v4.1 38 / 1,613,984 alleles AF 2.35e-05 · 0 homozygotes · FAF 2.31e-05
gnomAD v2.1 2 / 282,126 alleles AF 7.09e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.4e-05 · 38 / 1,613,984 alleles · 0 hom · FAF 2.3e-05
European (non-Finnish)37 / 1,179,958 3.1e-05
Remaining individuals1 / 62,482 1.6e-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 7.1e-06 · 2 / 282,126 alleles · 0 hom
European (non-Finnish)2 / 128,536 1.6e-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= 2.35442e-05; MAF= 0.00235%, 38/1613984 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.1357e-05; MAF= 0.00314%, 37/1179958 alleles, homozygotes = 0); grpmax FAF= 2.314e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.08903e-06; MAF= 0.00071%, 2/282126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55598e-05; MAF= 0.00156%, 2/128536 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.025

Other predictors

REVEL
0.572
BayesDel
0.333

How the predictions were used

PP3 Not assessed: SpliceAI returned no score, while REVEL 0.572 is below the generic PP3 supporting threshold of 0.644. Details ▾Hide ▴
Reasoning

PP3 is applicable because NM_001127510.3:c.6196A>G is a missense variant, p.(Arg2066Gly). The APC VCEP specifies PP3 at Supporting strength when multiple in silico splicing predictors support a deleterious effect, including use of in silico splicing predictors for presumed missense variants to identify possible splicing effects. SpliceAI returned no score, which is missing data and cannot be treated as a zero or as evidence against splice impact. The available Pangolin scores are not calibrated for PP3/BP4 in this assessment. REVEL is 0.572, below the generic PP3 Supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), and BayesDel has no generic ACMG strength calibration; neither therefore establishes PP3 under the governing APC specification. The criterion cannot be assessed definitively without an applicable calibrated splice-prediction result or other governing-VCEP-supported computational evidence.

Rule
APC VCEP Version 2.1: PP3 Supporting—missense variants should use in silico splicing predictors to reveal possible splicing effects; non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • The variant is missense: NM_001127510.3:c.6196A>G, NP_001120982.1:p.(Arg2066Gly), so PP3 is within scope.
  • The APC VCEP Version 2.1 PP3 rule states that presumed missense variants should be evaluated with in silico splicing predictors and that multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
  • SpliceAI returned no scores and max delta is null; this is missing data, not a score of 0 and not evidence of absent splice impact.
  • Pangolin scores are present (SG 0.025 and SL -0.001), but Pangolin is not calibrated for PP3/BP4 in this assessment.
  • REVEL score 0.572 is below the generic PP3 Supporting threshold of 0.644 from the ClinGen SVI REVEL calibration by Pejaver et al. 2022 (PMID:36413997).
  • BayesDel score 0.333397 is not usable for PP3 strength because no generic ACMG/AMP calibration is established and the APC VCEP does not specify a BayesDel cutoff.
Still missing
  • No SpliceAI score is available for this variant.
  • No multiple calibrated in silico splicing-predictor result supporting a deleterious effect is available.
Sources
cspec ↗spliceai ↗revelbayesdel
BP4 N/ANot applicable: APC VCEP excludes missense variants from BP4, which is limited to synonymous or intronic splice-impact assessment. Details ▾Hide ▴
Reasoning

BP4 is not applicable because the variant is missense, p.(Arg2066Gly). The governing APC VCEP explicitly states that BP4 is not applicable to missense variants; its BP4 rule is limited to synonymous or intronic variants with multiple in silico splicing predictors suggesting no impact. Per scope, predictor scores were not evaluated for BP4.

Rule
APC VCEP Version 2.1: BP4 is not applicable for missense variants; synonymous or intronic variants require multiple in silico splicing predictors suggesting no impact.
Evidence considered
  • The variant consequence is missense, NP_001120982.1:p.(Arg2066Gly).
  • The APC VCEP Version 2.1 BP4 rule explicitly states: missense variants—BP4 is not applicable.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or intronic variants, whereas this variant causes the missense change p.(Arg2066Gly). Details ▾Hide ▴
Reasoning

BP7 is not applicable because the variant is missense, p.(Arg2066Gly), rather than synonymous or intronic. The APC VCEP limits BP7 to synonymous or intronic variants at or beyond +7/-21 with multiple splicing algorithms predicting no splice impact. Per scope, splicing predictors were not evaluated for this out-of-scope criterion.

Rule
APC VCEP Version 2.1: BP7 Supporting applies only to synonymous or intronic variants at or beyond +7/-21 with multiple splicing prediction algorithms predicting no impact.
Evidence considered
  • The variant consequence is missense, NP_001120982.1:p.(Arg2066Gly), not synonymous or intronic.
  • The APC VCEP Version 2.1 BP7 rule applies to synonymous or intronic variants at or beyond +7/-21 with multiple splicing algorithms predicting no impact.
Sources
cspec ↗

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.572. BayesDel score = 0.333397.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.
    Church J et al. · 2001
    No paper-specific finding is recorded.
    PMID 11598466 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.
    Azzopardi D et al. · 2008
    The paper explicitly lists APC R2066G as a rare inherited nonsynonymous variant identified in one non-FAP, non-MUTYH-associated polyposis patient with multiple colorectal adenomas. It does not report a pathogenic or likely pathogenic alternate missense variant at Arg2066, nor a variant-specific functional assay, segregation result, or population-frequency result for R2066G.
    Names this variant
    PMID 18199528 ↗
    Quoted passage
    A1446T, K1454E, P1467S, A1474T, I1572T, P1934L, R2066G, I2329V, G2502S (10), I2541V, I2756V 35 of 201 (17.4%)

    Table 1, Non-FAP non-MAP patients, Multiple CRAs (number unknown), APC ORF

  • Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
    Minde DP et al. · 2011
    No paper-specific finding is recorded.
    PMID 21859464 ↗
  • 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
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • 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 ↗
  • ACG clinical guideline: Genetic testing and management of hereditary gastrointes
    No paper-specific finding is recorded.
    PMID 25645574 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint co
    No paper-specific finding is recorded.
    PMID 25741868 ↗

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

gnomAD v4.1 38 / 1,613,984 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar 9 Uncertain significance · 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= 2.35442e-05; MAF= 0.00235%, 38/1613984 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.1357e-05; MAF= 0.00314%, 37/1179958 alleles, homozygotes = 0); grpmax FAF= 2.314e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.08903e-06; MAF= 0.00071%, 2/282126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55598e-05; MAF= 0.00156%, 2/128536 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 188063)

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.572. BayesDel score = 0.333397.

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; COSV104567844, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.