About APC
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
APC c.295C>T, p.(Arg99Trp)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
The VCEP BS1 threshold is gnomAD Popmax Filtering AF ≥ 0.001% (0.00001). The gnomAD v2.1 grpmax FAF is 0.063% (0.00063466), approximately 63-fold above the BS1 threshold. Additionally, gnomAD v4.1 shows 1,256 alleles including 1 homozygote (grpmax FAF 0.095%), further supporting that this variant is too common in population databases for a fully penetrant APC-associated disorder.
BP1Supporting
BP1 · supporting
APC is a gene where truncating (loss-of-function) variants are the predominant disease mechanism. The variant p.Arg99Trp is a missense change at codon 99, which lies outside the excluded region (codons 1021–1035, the first 15-amino acid repeat of the β-catenin binding domain). BP1 is applicable per VCEP rules.
BP6Supporting
BP6 · supporting
Expert panel ClinVar expert panel classified as Benign.
Recorded classification: Likely benign
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 v2.1 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BS1 strong benign, BP1 supporting benign, BP6 supporting benign; maps to Likely Benign.
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
1,256 / 1,613,920 alleles
gnomAD v4.1: 1,256 / 1,613,920 alleles. Recorded AF 0.000778229. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000399511; MAF= 0.03995%, 113/282846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000735465; MAF= 0.07355%, 95/129170 alleles, homozygotes = 0); grpmax FAF= 0.00063466.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded. ClinVar API review status: reviewed by expert panel.
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
14 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57367627, n = 14 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen APC VCEP v2.1, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
BS1_Strong is met: the variant has a gnomAD v2.1 grpmax filtering allele frequency of 0.063% (0.00063466), approximately 63-fold above the VCEP BS1 threshold of ≥0.001% (0.00001). This is also supported by gnomAD v4.1 with 1,256 alleles (grpmax FAF 0.095%) including one homozygote.
BP1_Supporting is met: the variant is a missense change (p.Arg99Trp) in APC, a gene where truncating variants are the predominant disease mechanism. Codon 99 is outside the excluded region (codons 1021–1035, the first 15-amino acid repeat of the β-catenin binding domain).
Per the APC VCEP rules for combining criteria, the fulfillment of one Benign-Strong criterion (BS1) reaches a classification of Likely Benign. The additional BP1_Supporting criterion reinforces this assessment.
This variant is classified as Benign in ClinVar (Variation ID: 135695) with review status 'reviewed by expert panel,' consistent with the VCEP-based assessment here.
No criteria match.
Met · 3
BS1 StrongThe VCEP BS1 threshold is gnomAD Popmax Filtering AF ≥ 0.001% (0.00001). The gnomAD v2.1 grpmax FAF is 0.063% (0.00063466), approximately 63-fold above the BS1 threshold. Additionally, gnomAD v4.1 shows 1,256 alleles including 1 homozygote (grpmax FAF 0.095%), further supporting that this variant is too common in population databases for a fully penetrant APC-associated disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF: 0.00063466 (0.063%) >> VCEP BS1 threshold 0.001%
- gnomAD v4.1: 1
- 256 alleles
- 1 homozygote
- grpmax FAF 0.00094937 (0.095%)
- Total AF in v2.1: 113/282
- 846 alleles (0.04%)
Sources
BP1 SupportingAPC is a gene where truncating (loss-of-function) variants are the predominant disease mechanism. The variant p.Arg99Trp is a missense change at codon 99, which lies outside the excluded region (codons 1021–1035, the first 15-amino acid repeat of the β-catenin binding domain). BP1 is applicable per VCEP rules. Details ▾Hide ▴
Evidence considered
- APC VCEP: BP1 applicable to missense variants except codons 1021-1035
- Codon 99 is outside the excluded β-catenin binding domain repeat region
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
Not met · 15 · evaluated, threshold not reached
PS1 No previously established pathogenic or likely pathogenic missense variant resulting in the same amino acid change (p.Arg99Trp) has been identified. The only VCEP-recognized LP missense variants in APC are c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg), both at codons distant from codon 99. Details ▾Hide ▴
Evidence considered
- APC VCEP v2.1: no missense variant classified as Pathogenic
- only two LP missense variants at codons 1026 and 1028
Sources
PS2 No de novo observations with confirmed parentage are available for this variant in the evidence. Details ▾Hide ▴
Evidence considered
- No de novo data found in ClinVar
- literature
- or case evidence
Still missing
- No proband-level data available for de novo assessment
PS3 No variant-specific functional data available. The variant (codon 99) lies outside the APC β-catenin binding domain (codons 959–2129) where protein functional assays could be applicable per VCEP rules. No RNA assay data exists, and OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
PS4 No proband or phenotype data available to assess prevalence in affected individuals versus controls. No phenotype points can be assigned per VCEP Table 1. Details ▾Hide ▴
Evidence considered
- No proband-level phenotype data in evidence
Still missing
- No case-level phenotype or proband data
PM2 The VCEP PM2_Supporting threshold for allele count > 1 requires allele frequency ≤ 0.0003% (0.000003). This variant has gnomAD v2.1 AF of 0.04% (113/282,846 alleles), far exceeding the threshold. The variant is too common in population databases to qualify as rare in controls. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF 0.0003995 (113/282
- 846 alleles
- 0 homozygotes)
- gnomAD v4.1: AF 0.000778 (1
- 256/1
- 613
- 920 alleles
- 1 homozygote)
- VCEP PM2 threshold for AC>1: ≤0.000003
- observed AF 0.0004 >> threshold
Sources
PM5 No known pathogenic or likely pathogenic missense variant at codon 99 (p.Arg99) exists. The only VCEP-recognized LP missense variants in APC are at codons 1026 (p.Asn1026Ser) and 1028 (p.Ser1028Arg). No comparator missense variant at the same residue meets PM5 criteria. Details ▾Hide ▴
PM6 No assumed de novo observations (without confirmed parentage) are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar
- literature
- or case evidence
Still missing
- No proband-level data for de novo assessment
PP1 No co-segregation data available. No family studies with meiotic segregation counts are present in the evidence. Details ▾Hide ▴
Evidence considered
- No family segregation data in evidence
Still missing
- No co-segregation or family study data
PP3 The APC VCEP restricts PP3 for missense variants to in silico splicing predictors only. SpliceAI predicts no significant splice impact (max delta score = 0.07), and no other splicing predictors suggest a deleterious splicing effect. Computational prediction models for conservation or evolution are not used per VCEP rules. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.07 (no significant splice impact)
- VCEP PP3 for missense: only splicing predictors applicable
Sources
BA1 The VCEP BA1 threshold is gnomAD Popmax Filtering AF ≥ 0.1% (0.001). The gnomAD v2.1 grpmax FAF is 0.063% (0.00063466), which is below the BA1 threshold. The gnomAD v4.1 grpmax FAF of 0.095% (0.00094937) also falls below the threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF: 0.00063466 (0.063%)
- gnomAD v4.1 grpmax FAF: 0.00094937 (0.095%)
- VCEP BA1 threshold: ≥0.1% (0.001)
- both datasets below threshold
Sources
BS2 No individual-level healthy phenotype data meeting VCEP criteria is available. The VCEP requires ≥10 points for healthy individuals (age ≥50, <5 adenomatous polyps, absence of Table 1 features) or ≥2 homozygous observations. The gnomAD v4.1 single homozygote is insufficient for BS2 (threshold is ≥2). The VCEP explicitly states gnomAD non-cancer dataset cannot be used to count heterozygous healthy individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 homozygote (insufficient for ≥2 threshold)
- VCEP BS2: gnomAD non-cancer dataset not usable for heterozygous healthy individuals
Still missing
- No individual-level healthy phenotype data
Sources
BS3 No functional studies demonstrating no damaging effect are available. The variant at codon 99 lies outside the APC β-catenin binding domain (codons 959–2129), where protein-level functional assays could be applicable per VCEP BS3_Supporting. No RNA assay data in constitutional patient samples exists for this missense variant. Details ▾Hide ▴
Evidence considered
- Codon 99 is outside β-catenin binding domain (959-2129) for VCEP BS3 protein assays
- No RNA assay data available
Still missing
- No BS3-qualifying functional studies for this variant
Sources
BS4 No non-segregation data available. No affected family members without the variant have been reported with quantifiable phenotype points. Details ▾Hide ▴
Evidence considered
- No family-level segregation or non-segregation data in evidence
Still missing
- No family studies for non-segregation analysis
BP2 The variant has not been observed in trans with a pathogenic or likely pathogenic APC variant, nor has it been observed ≥3 times in unknown phase with different P/LP APC variants. Details ▾Hide ▴
Evidence considered
- No trans or cis phase data with P/LP APC variants available
Still missing
- No phase data with other APC variants
BP5 No alternate genetic basis for colorectal polyposis has been identified in association with this variant. The VCEP requires a (likely) pathogenic variant in another adenomatous polyposis gene (POLD1, POLE, MUTYH, NTHL1, MSH3, or mismatch repair genes) for BP5 application. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis documented
Still missing
- No data on alternate genetic basis for phenotype
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.295C>T, p.Arg99Trp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice) per the APC VCEP Figure 1 decision tree. This variant does not fall into any PVS1 bucket. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution in exon 5
- not a null variant
Sources
vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PM1 VCEPThe APC VCEP states PM1 is not applicable. No mutational hotspots or critical functional domains without benign variation have been established for APC. Details ▾Hide ▴
Evidence considered
- APC VCEP v2.1: PM1 listed as Not Applicable
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP2 VCEPThe APC VCEP states PP2 is not applicable. Missense variants are not a frequent mechanism of disease in APC; truncating variants are the predominant pathogenic mechanism. Details ▾Hide ▴
PP4 VCEPThe APC VCEP states PP4 is not applicable. The patient's phenotype or family history specificity is already captured by the PS4 specifications. Details ▾Hide ▴
PP5 VCEPThe APC VCEP states PP5 is not for use, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP4 N/AThe APC VCEP explicitly states BP4 is not applicable for missense variants. BP4 is reserved for synonymous or intronic variants where multiple in silico splicing predictors suggest no impact. Details ▾Hide ▴
BP7 N/ABP7 is reserved for synonymous (silent) or intronic variants at or beyond +7/−21 splice positions. This variant (c.295C>T) is a missense substitution and does not meet BP7 applicability criteria. Details ▾Hide ▴
PS5 N/APS5 is not defined in the APC VCEP framework and is not a standard ACMG/AMP 2015 criterion. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- APC
- Transcript
- NM_001127510.3
- Coding (HGVS c.)
- NM_001127510.3:c.295C>T
- Protein (HGVS p.)
- NP_001120982.1:p.(Arg99Trp)
- GRCh38
- chr5:112767263 C>T
- GRCh37
- chr5:112102960 C>T
- COSMIC
- COSV57367627
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in APC
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1,256 / 1,613,920 alleles
AF 0.000778 · 1 homozygotes · FAF 0.000949
gnomAD v2.1
113 / 282,846 alleles
AF 0.0004 · 0 homozygotes · FAF 0.000635
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00078 · 1256 / 1,613,920 alleles · 1 hom · FAF 0.00095
| European (non-Finnish)1177 / 1,180,018 | 0.0011 hom |
| Remaining individuals47 / 62,480 | 0.00075 |
| African/African American22 / 74,880 | 0.00029 |
| Admixed American5 / 59,982 | 8.3e-05 |
| European (Finnish)3 / 64,000 | 4.7e-05 |
| East Asian2 / 44,886 | 4.5e-05 |
0 alternate alleles recorded in 4 other groups: Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0004 · 113 / 282,846 alleles · 0 hom · FAF 0.00063
| European (non-Finnish)95 / 129,170 | 0.00074 |
| African/African American9 / 24,968 | 0.00036 |
| Remaining individuals2 / 7,224 | 0.00028 |
| European (Finnish)3 / 25,118 | 0.00012 |
| Admixed American3 / 35,436 | 8.5e-05 |
| East Asian1 / 19,944 | 5e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000778229; MAF= 0.07782%, 1256/1613920 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000997442; MAF= 0.09974%, 1177/1180018 alleles, homozygotes = 1); grpmax FAF= 0.00094937.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000399511; MAF= 0.03995%, 113/282846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000735465; MAF= 0.07355%, 95/129170 alleles, homozygotes = 0); grpmax FAF= 0.00063466.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.587
- BayesDel
- 0.275
How the predictions were used
PP3 The APC VCEP restricts PP3 for missense variants to in silico splicing predictors only. SpliceAI predicts no significant splice impact (max delta score = 0.07), and no other splicing predictors suggest a deleterious splicing effect. Computational prediction models for conservation or evolution are not used per VCEP rules. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.07 (no significant splice impact)
- VCEP PP3 for missense: only splicing predictors applicable
Sources
BP4 N/AThe APC VCEP explicitly states BP4 is not applicable for missense variants. BP4 is reserved for synonymous or intronic variants where multiple in silico splicing predictors suggest no impact. Details ▾Hide ▴
BP7 N/ABP7 is reserved for synonymous (silent) or intronic variants at or beyond +7/−21 splice positions. This variant (c.295C>T) is a missense substitution and does not meet BP7 applicability criteria. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.587. BayesDel score = 0.275108.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1,256 / 1,613,920 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.070
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1529292791
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001127510.3%3Ac.295C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-112102960-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-112767263-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-112767263-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127510.3%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/APC/R99W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122364346
- Cancer hotspots ↗www.cancerhotspots.org/
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= 0.000778229; MAF= 0.07782%, 1256/1613920 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000997442; MAF= 0.09974%, 1177/1180018 alleles, homozygotes = 1); grpmax FAF= 0.00094937.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000399511; MAF= 0.03995%, 113/282846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000735465; MAF= 0.07355%, 95/129170 alleles, homozygotes = 0); grpmax FAF= 0.00063466.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
ClinVar
This variant is present in ClinVar (Variation ID: 135695); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.587. BayesDel score = 0.275108.
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; COSV57367627, n = 14 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.