About APC
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
APC c.608A>G, p.(Gln203Arg)
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.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1 (0/1,613,130 alleles), and gnomAD-Canada. Per the APC VCEP, PM2_Supporting applies when allele frequency is below the defined threshold: AF ≤ 0.0003% if AC > 1, or AF < 0.001% if AC ≤ 1. The variant meets this criterion as it is entirely absent from population databases.
Benign criteria applied · 1
BP1Supporting
BP1 · supporting
BP1 applies to missense variants in APC, a gene for which primarily truncating variants are known to cause disease. The APC VCEP states BP1 is applicable with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). This variant (p.Gln203Arg) is at codon 203, well outside that excluded region. SpliceAI confirms no cryptic splicing (max delta 0.01).
Recorded classification: Uncertain significance
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 was evaluated deterministically with applied criteria: PM2 supporting, BP1 supporting benign; no rule matched the adjudicated criteria.
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
0 / 1,613,130 alleles
gnomAD v4.1: 0 / 1,613,130 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions
6 Uncertain significance · 1 Uncertain Significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 2 met · 16 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
NM_001127510.3:c.608A>G (p.Gln203Arg) is a missense variant in APC, a tumor suppressor gene where loss of function is the established disease mechanism for familial adenomatous polyposis.
The variant is absent from gnomAD v2.1, v4.1 (0/1,613,130 alleles), and gnomAD-Canada, meeting the APC VCEP PM2_Supporting criterion for rarity in population controls.
BP1 (supporting benign) is met: APC is a gene where primarily truncating variants cause disease, and this missense variant lies outside the excluded β-catenin binding domain region (codons 1021-1035). SpliceAI (max delta 0.01) shows no cryptic splice effect.
PVS1 is not met as this is a missense variant, not a null variant eligible under the APC VCEP decision tree.
No functional studies (PS3/BS3), de novo observations (PS2/PM6), segregation data (PP1/BS4), phenotype points (PS4), or pathogenic missense comparators at codon 203 (PM5) are available.
ClinVar reports this variant as Uncertain Significance (criteria provided, single submitter). No expert panel submission exists.
Per the APC VCEP Rules for Combining Criteria, a variant fulfilling only PM2_Supporting without any other pathogenic criterion remains a Variant of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1 (0/1,613,130 alleles), and gnomAD-Canada. Per the APC VCEP, PM2_Supporting applies when allele frequency is below the defined threshold: AF ≤ 0.0003% if AC > 1, or AF < 0.001% if AC ≤ 1. The variant meets this criterion as it is entirely absent from population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1 (0/1
- 613
- 130 alleles)
- Absent from gnomAD-Canada
Sources
BP1 SupportingBP1 applies to missense variants in APC, a gene for which primarily truncating variants are known to cause disease. The APC VCEP states BP1 is applicable with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). This variant (p.Gln203Arg) is at codon 203, well outside that excluded region. SpliceAI confirms no cryptic splicing (max delta 0.01). Details ▾Hide ▴
Evidence considered
- APC is a gene where primarily truncating variants cause disease (FAP)
- Variant is missense at codon 203
- outside the excluded β-catenin domain region (codons 1021-1035)
- SpliceAI shows no splicing impact
- supporting classification as a true missense
Sources
Not met · 16 · evaluated, threshold not reached
PVS1 NM_001127510.3:c.608A>G is a missense variant (p.Gln203Arg), not a null variant. PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice) per the APC VCEP decision tree (Figure 1). The variant does not fall into any PVS1-eligible bucket. Details ▾Hide ▴
Evidence considered
- Missense variant at codon 203 is not a null variant
- APC VCEP PVS1 decision tree (Fig. 1) does not include this variant in any PVS1 list (A-D)
Sources
PS1 PS1 requires the same amino acid change as a previously established pathogenic or likely pathogenic variant. According to the APC VCEP, there are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). No missense variant has been classified as Pathogenic. The p.Gln203Arg change has not been previously classified as pathogenic or likely pathogenic. Details ▾Hide ▴
PS2 No de novo observations have been reported for this variant. The APC VCEP PS2 criterion requires de novo scores (≥1 for moderate), but no de novo data for NM_001127510.3:c.608A>G were identified in the literature or ClinVar submissions. Details ▾Hide ▴
PS3 No well-established in vitro or in vivo functional studies have been reported for NM_001127510.3:c.608A>G (p.Gln203Arg). The variant lies outside the β-catenin binding domain (codons 959-2129), so the VCEP protein assay pathway (β-catenin regulated transcription) does not apply. No RNA assay data are available for this missense variant. The literature search identified no variant-specific functional evidence. Details ▾Hide ▴
PS4 No phenotype points can be assigned. The APC VCEP PS4 criterion requires quantification of affected individuals using phenotype points (≥1 point for supporting). No proband-specific clinical data with adenomatous polyposis phenotype were identified in the literature or ClinVar submissions for this variant. The ClinVar PMIDs are guideline/review papers, not case reports. Details ▾Hide ▴
PM5 PM5 requires a different pathogenic or likely pathogenic missense change at the same amino acid residue. The APC VCEP recognizes only two LP missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). No pathogenic or likely pathogenic missense variant has been reported at codon 203 (Gln203). The ClinVar classification for this variant itself is VUS. Details ▾Hide ▴
PM6 No assumed de novo observations have been reported. The APC VCEP PM6 criterion requires de novo scores (≥0.5 for supporting), but no de novo data were identified in the literature or ClinVar submissions. Details ▾Hide ▴
PP1 No co-segregation data have been reported for this variant. The APC VCEP PP1 criterion requires segregation in 3-4 meioses for supporting strength. No segregation studies were identified in the literature. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies have assessed segregation of this variant
Sources
PP3 The APC VCEP states that for missense variants, computational prediction models for conservation and evolution should not be used. Only in silico splicing predictors may be applied. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL (0.426) and BayesDel (0.206) are not used per VCEP guidance for missense variants. No multiple lines of splicing evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splicing impact)
- REVEL 0.426 and BayesDel 0.206 not applicable per VCEP for missense variants
Sources
BA1 The APC VCEP BA1 threshold is a gnomAD Popmax Filtering Allele Frequency ≥ 0.1% (0.001). This variant is absent from gnomAD v2.1, v4.1 (0/1,613,130 alleles), and gnomAD-Canada. The allele frequency of 0.0 does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD allele frequency = 0.0
- below BA1 threshold of ≥0.1%
Sources
BS1 The APC VCEP BS1 threshold is a gnomAD Popmax Filtering Allele Frequency ≥ 0.001% (0.00001). This variant is absent from gnomAD v2.1 and v4.1. The allele frequency of 0.0 does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD allele frequency = 0.0
- below BS1 threshold of ≥0.001%
Sources
BS2 No healthy adult individuals carrying this variant have been reported. The APC VCEP BS2 requires ≥3 points for healthy individuals (supporting) or ≥10 points (strong), with points defined by age ≥50, <5 adenomatous polyps, and absence of FAP features. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
- No healthy individual data available
Still missing
- No data on variant presence in healthy individuals aged ≥50
Sources
BS3 No well-established functional studies show no damaging effect. The APC VCEP BS3 requires RNA assays demonstrating no mRNA aberration (for synonymous/intronic variants) or protein assays showing retention of β-catenin regulated transcription (for variants within codons 959-2129). This missense variant at codon 203 is outside the β-catenin binding domain, and no functional studies have been reported. Details ▾Hide ▴
Evidence considered
- No functional studies identified
- Variant is outside β-catenin binding domain (codons 959-2129)
- so protein assay pathway does not apply
Still missing
- No functional characterization of p.Gln203Arg
Sources
BS4 No data on lack of segregation in affected family members. The APC VCEP BS4 requires affected members without the variant scoring phenotype points. No segregation or family studies were identified for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies to assess non-segregation
Sources
BP2 No evidence of this variant observed in trans with a (likely) pathogenic APC variant, nor observed ≥3 times in unknown phase with different (likely) pathogenic APC variants. The APC VCEP BP2 criterion requires such observations. Details ▾Hide ▴
Evidence considered
- No trans or co-occurrence data available
Still missing
- No phase data with other APC variants
Sources
BP5 BP5 requires an alternate genetic basis for the colorectal polyposis phenotype (e.g., a pathogenic variant in POLD1, POLE, MUTYH, NTHL1, MSH3, or mismatch repair genes). No such alternate molecular diagnosis has been reported in any individual carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis reported
Still missing
- No data on alternate genetic findings in carriers
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 VCEPThe APC VCEP has determined that PM1 is not applicable for APC. The supplementary material states: 'Based on our knowledge there are no mutational hotspots or critical functional domains in APC.' Cancerhotspots.org also reports this residue is not a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- VCEP states PM1 not applicable for APC
- Residue 203 is not a statistically significant hotspot
Sources
PP2 VCEPThe APC VCEP marks PP2 as Not Applicable. Missense variants are not a frequent mechanism of disease in APC, which is primarily a truncating-variant disease gene. Details ▾Hide ▴
PP4 VCEPThe APC VCEP marks PP4 as Not Applicable. The supplementary material states that PP4 is already captured by the specifications of PS4, and is therefore not used independently. Details ▾Hide ▴
PP5 VCEPThe APC VCEP marks PP5 as Not Applicable, following the recommendation of Biesecker et al. 2018. Additionally, this variant is classified as Uncertain Significance in ClinVar (criteria provided, single submitter), not as pathogenic. Details ▾Hide ▴
BP4 N/AThe APC VCEP explicitly states that BP4 is not applicable for missense variants. The supplementary material notes: 'BP4 is not applicable for missense variants according to the APC VCEP.' Details ▾Hide ▴
BP6 VCEPThe APC VCEP marks BP6 as Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP: BP6 is not for use as recommended by ClinGen SVI VCEP Review Committee
Sources
BP7 N/ABP7 is applicable only to synonymous (silent) or intronic variants at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact. NM_001127510.3:c.608A>G is a missense variant (p.Gln203Arg), not synonymous or intronic. Details ▾Hide ▴
PS5 N/APS5 is not a recognized ACMG/AMP criterion code. The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5. The equivalent criterion for reputable source reporting a variant as pathogenic is PP5, which the APC VCEP explicitly marks as Not Applicable. Details ▾Hide ▴
Identifiers
- Gene
- APC
- Transcript
- NM_001127510.3
- Coding (HGVS c.)
- NM_001127510.3:c.608A>G
- Protein (HGVS p.)
- NP_001120982.1:p.(Gln203Arg)
- GRCh38
- chr5:112780866 A>G
- GRCh37
- chr5:112116563 A>G
- ClinVar
- 819262, 470035
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
0 / 1,613,130 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,613,130 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613130 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75044 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.426
- BayesDel
- 0.206
How the predictions were used
PP3 The APC VCEP states that for missense variants, computational prediction models for conservation and evolution should not be used. Only in silico splicing predictors may be applied. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL (0.426) and BayesDel (0.206) are not used per VCEP guidance for missense variants. No multiple lines of splicing evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splicing impact)
- REVEL 0.426 and BayesDel 0.206 not applicable per VCEP for missense variants
Sources
BP4 N/AThe APC VCEP explicitly states that BP4 is not applicable for missense variants. The supplementary material notes: 'BP4 is not applicable for missense variants according to the APC VCEP.' Details ▾Hide ▴
BP7 N/ABP7 is applicable only to synonymous (silent) or intronic variants at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact. NM_001127510.3:c.608A>G is a missense variant (p.Gln203Arg), not synonymous or intronic. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.426. BayesDel score = 0.206025.
6 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
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is the foundational guideline paper establishing the variant classification framework. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
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PMID 11598466 ↗Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.Church J et al. · 2001ASCRS practice parameters for identification and testing of patients at risk for dominantly inherited colorectal cancer. Discusses FAP, HNPCC, and genetic testing strategies at the syndrome level. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. Discusses the policy framework for secondary findings. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015ACMG policy statement updating recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Provides tables of cancer types and referral criteria for hereditary cancer syndromes including FAP. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
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PMID 35802134 ↗ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing. Lists APC as a gene for which pathogenic and likely pathogenic variants should be reported. NM_001127510.3:c.608A>G (p.Gln203Arg) was not mentioned in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,613,130 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
6 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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1529292791
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/470035/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-112116563-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-112780866-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-112780866-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127510.3%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/APC/Q203R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=APC+c.608A%3EG
- 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; MAF= 0.00000%, 0/1613130 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75044 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 470035)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.426. BayesDel score = 0.206025.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.