0%
APCc.2204C>TLikely benign
Print report
Variant interpretation report

APC c.2204C>T, p.Ala735Val

NM_001127510.3:c.2204C>T NP_001120982.1:p.(Ala735Val) Missense · exon 17 View identifiers
Classification
Likely benign

Variant description:

The APC NM_001127510.3:c.2204C>T (NP_001120982.1:p.(Ala735Val)) missense variant has previously been reported in somatic cancers (COSMIC; COSV57326152, n = 2 times). Based on available guidelines, this variant is considered to be Likely Benign.

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: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BS1Strong
BS1 · strong

Met at Strong: non-cancer gnomAD v2.1 exome Popmax FAF is 0.004594%, exceeding the APC VCEP BS1 threshold of at least 0.001%.

BP1Supporting
BP1 · supporting

Met, supporting: codon 735 is outside the VCEP BP1 exception at codons 1021–1035 for APC missense variants.

BP2Supporting
BP2 · supporting

Met at Supporting: c.2204C>T was observed once in trans with pathogenic APC p.Arg332Ter (c.994C>T).

Recorded classification: Likely benign

Likely Benign: BS1 (strong) satisfies the APC VCEP benign strong-evidence rule, while BP1 and BP2 (supporting) independently satisfy its two-supporting-evidence rule.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
115 / 1,613,948 alleles

gnomAD v4.1: 115 / 1,613,948 alleles. Recorded AF 7.12538e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.04161e-05; MAF= 0.00604%, 17/281382 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000201045; MAF= 0.02010%, 4/19896 alleles, homozygotes = 0); grpmax FAF= 4.426e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.001086130118388183, 20/18414 alleles, homozygotes = 0).

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

Recorded REVEL score: 0.250. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
11 reported laboratory submissions

7 Likely benign · 3 Benign · 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
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57326152, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 3 met · 6 not met · 6 not assessed · 13 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

All three requested consequence/LOF criteria are not applicable under the APC VCEP: PVS1 is restricted to null variants, while PM4 and BP3 are explicitly not used by the VCEP.

For the requested codon/residue/domain criteria, BP1_Supporting is met because codon 735 is outside the APC VCEP BP1 exception at codons 1021-1035.

PS1, PM1, and PM5 are not applicable under the APC VCEP's residue and hotspot restrictions, while PP2 is not met because APC missense variants are not a frequent disease mechanism under the VCEP specification.

Within this criterion group, PP4, PP5, and BP6 are unavailable under the APC VCEP rules; PS4 cannot be assessed without phenotype-point data; BP5 is not met because the reported second variant is in APC rather than another adenomatous polyposis gene.

Met · 3

BS1 StrongVCEPMet at Strong: non-cancer gnomAD v2.1 exome Popmax FAF is 0.004594%, exceeding the APC VCEP BS1 threshold of at least 0.001%. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS1 at a Popmax Filtering Allele Frequency of at least 0.001%, preferably using the gnomAD v2.1.1 non-cancer dataset. The governing non-cancer exome data show APC c.2204C>T (p.Ala735Val; p.A735V) with exome Popmax FAF 4.594e-05 (0.004594%), which exceeds 0.00001 (0.001%). Therefore BS1 is met at Strong strength. The exact variant notations c.2204C>T, p.Ala735Val, and p.A735V were searched in APC_specifications_supplementary-material_V2.pdf.txt and no variant-specific table entry was found; this does not indicate absence of population evidence.

VCEP rule
Allele frequency ≥ 0.001% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))
Evidence considered
  • APC VCEP BS1 specification: Popmax Filtering Allele Frequency threshold ≥0.001%, preferably from the gnomAD v2.1.1 non-cancer dataset.
  • gnomAD v2.1 non-cancer exomes for APC c.2204C>T (p.Ala735Val; p.A735V): exome Popmax FAF 4.594e-05 (0.004594%), AF 5.93814e-05 (0.00594%), allele count 14/235764, homozygotes 0.
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt after searching all three notations; this is a reference-file search gap, not evidence absence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BP1 SupportingVCEPMet, supporting: codon 735 is outside the VCEP BP1 exception at codons 1021–1035 for APC missense variants. Details ▾Hide ▴
Reasoning

The APC VCEP states that APC is primarily affected by truncating disease-causing variants and excludes BP1 only for missense variants in codons 1021-1035, the first 15-amino-acid repeat of the β-catenin binding domain. p.Ala735Val is a missense variant at codon 735, outside the exception, so BP1_Supporting applies. The variant was also reported as likely benign in the Mayo Clinic APC cohort and observed once in trans with p.Arg332Ter, but that paper is supportive context rather than the governing BP1 rule.

VCEP rule
APC is a gene for which primarily truncating variants are known to cause disease. Based on our knowledge there are only two amino acid positions (1026 and 1028), where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) (for details see PS1). Therefore, for all variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) BP1 is not allowed to be used.
Evidence considered
  • APC VCEP CSPEC BP1 rule: BP1 applies to APC except for missense variants in the first 15-amino-acid repeat of the β-catenin binding domain, codons 1021-1035.
  • APC_specifications_supplementary-material_V2.pdf, BP1 row: APC is primarily a truncating-variant disease gene, and BP1 is not allowed only for variants in codons 1021-1035.
  • The assessed variant is missense p.(Ala735Val) at codon 735, outside codons 1021-1035.
  • Kerr et al. 2013, Table 2 and family-testing results: c.2204C>T p.Ala735Val was listed among likely benign APC variants and was seen once in trans with p.R332X.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗PMID:23159591 ↗
BP2 SupportingVCEPMet at Supporting: c.2204C>T was observed once in trans with pathogenic APC p.Arg332Ter (c.994C>T). Details ▾Hide ▴
Reasoning

The APC c.2204C>T (p.Ala735Val) variant was observed once in trans with the pathogenic APC p.Arg332Ter (c.994C>T) variant in family testing. This directly satisfies the APC VCEP BP2 Supporting rule requiring observation in trans with a (Likely) Pathogenic APC variant.

VCEP rule
Observed _in trans_ with a (Likely) Pathogenic _APC_ variant **OR** ≥ 3 times in an unknown phase with different (Likely) Pathogenic _APC_ variants.
Evidence considered
  • Kerr et al. 2013, Table 2, likely benign APC variants, row c.2204C>T p.Ala735Val: listed with evidence designation "pt" and observed in one case.
  • Kerr et al. 2013, Results paragraph describing targeted APC mutation testing of family members: "A c.2204C>T missense variant was seen in trans with p.R332X once." Here p.R332X is APC p.Arg332Ter (c.994C>T), a pathogenic APC variant.
  • The APC VCEP BP2 Supporting rule is satisfied by the documented in-trans observation; the alternative unknown-phase count pathway is not needed.
Sources
cspec ↗PMID:23159591 ↗

Not met · 6 · evaluated, threshold not reached

PM2 VCEPNot met: non-cancer gnomAD v2.1 exome AF is 0.00594% with allele count 14, exceeding the APC VCEP PM2 threshold of 0.0003%. Details ▾Hide ▴
Reasoning

The APC VCEP defines PM2_Supporting as AF ≤0.0003% (0.000003) when allele count is greater than 1, or AF <0.001% (0.00001) when allele count is at most 1. The governing gnomAD v2.1 non-cancer exome record has allele count 14 and AF 5.93814e-05 (0.00594%), with Popmax FAF 4.594e-05 (0.004594%); it exceeds the applicable 0.0003% threshold. Therefore PM2 is not met. The exact variant notations c.2204C>T, p.Ala735Val, and p.A735V were searched in APC_specifications_supplementary-material_V2.pdf.txt and no variant-specific table entry was found; this does not indicate absence of population evidence.

VCEP rule
The allele frequency ≤ 0.0003% (0.000003) is used if the allele count is > 1. To tolerate the occurrence 1 x in gnomAD the VCEP has set an allele frequency < 0.001% (0.00001) (which is below BS1) if the allele count is ≤ 1.
Evidence considered
  • APC VCEP PM2 specification: AF ≤0.0003% (0.000003) when allele count is >1; AF <0.001% (0.00001) when allele count is ≤1.
  • gnomAD v2.1 non-cancer exomes for APC c.2204C>T (p.Ala735Val; p.A735V): AF 5.93814e-05 (0.00594%), allele count 14/235764, homozygotes 0; exome Popmax FAF 4.594e-05 (0.004594%).
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt after searching all three notations; this is a reference-file search gap, not evidence absence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
PP2 VCEPNot met: APC missense variants are not a frequent disease mechanism, and most are benign, likely benign, or VUS under the VCEP description. Details ▾Hide ▴
Reasoning

The APC VCEP specifically describes missense variants as not being a frequent mutation type in APC and states that the majority are benign, likely benign, or VUS in ClinVar/LOVD. Therefore the PP2 prerequisite that missense variants are a common mechanism of disease is not satisfied for this missense variant.

VCEP rule
Missense variants are not a frequent mutation type in APC. The majority of missense variants are regarded as benign / likely benign or VUS in ClinVar / LOVD. A few represent splice variants (Karabachev et al. 2020, PMID: 32750050) and low/moderate penetrant variants. Currently, there are only two amino acid positions with reported Likely Pathogenic missense variants (p.Asn1026 and p.Ser1028) (for details see PS1).
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PP2 row: missense variants are not a frequent mutation type in APC, and the majority are regarded as benign, likely benign, or VUS in ClinVar/LOVD; only two amino acid positions have reported Likely Pathogenic missense variants.
  • The assessed variant is a missense variant, NM_001127510.3:c.2204C>T p.(Ala735Val).
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PP3 VCEPNot met: SpliceAI maximum delta 0.00 predicts no significant splice impact, whereas APC missense PP3 requires splicing evidence revealing a possible effect. Details ▾Hide ▴
Reasoning

The APC VCEP limits PP3 for missense variants to in silico splicing prediction used to reveal a possible splicing effect; it does not permit conservation or other protein-impact predictors on this path. The available SpliceAI result predicts no significant splice impact, with a maximum delta score of 0.00, so the missense-specific PP3 path is not supported. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects. **Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.
Evidence considered
  • APC VCEP PP3 rule, cspec PP3 entry: for missense variants, do not use conservation/evolution computational prediction models; use in silico splicing predictors to reveal possible splicing effects.
  • SpliceAI Lookup for NM_001127510.3:c.2204C>T: max delta score 0.00; the case evidence states that SpliceAI predicts no significant splice impact.
  • APC_specifications_supplementary-material_V2.pdf, PP3 row: the APC VCEP-specific missense path is limited to in silico splicing prediction.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗spliceai ↗
BA1 VCEPNot met: non-cancer gnomAD v2.1 exome Popmax FAF is 0.004594%, below the APC VCEP BA1 threshold of at least 0.1%. Details ▾Hide ▴
Reasoning

The APC VCEP specifies BA1 at a Popmax Filtering Allele Frequency of at least 0.1%, preferably using the gnomAD v2.1.1 non-cancer dataset. In the governing non-cancer exome data, APC c.2204C>T (p.Ala735Val; p.A735V) has AF 5.93814e-05 (0.00594%; 14/235764 alleles), and the non-cancer exome Popmax FAF is 4.594e-05 (0.004594%), both below 0.001. Therefore BA1 is not met. The exact variant notations c.2204C>T, p.Ala735Val, and p.A735V were searched in APC_specifications_supplementary-material_V2.pdf.txt and no variant-specific table entry was found; this does not indicate absence of population evidence.

VCEP rule
Allele frequency ≥ 0.1% (preferably based on the Popmax Filtering Allele Frequency of the non-cancer dataset from gnomAD (v2.1.1))
Evidence considered
  • APC VCEP BA1 specification: Popmax Filtering Allele Frequency threshold ≥0.1%, preferably from the gnomAD v2.1.1 non-cancer dataset.
  • gnomAD v2.1 non-cancer exomes for APC c.2204C>T (p.Ala735Val; p.A735V): AF 5.93814e-05 (0.00594%), allele count 14/235764, homozygotes 0; exome Popmax FAF 4.594e-05 (0.004594%).
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt after searching all three notations; this is a reference-file search gap, not evidence absence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BS2 VCEPNot met: non-cancer gnomAD v2.1 exomes report zero homozygotes, and no VCEP-qualified healthy-individual phenotype points are available. Details ▾Hide ▴
Reasoning

The APC VCEP states that the gnomAD v2.1.1 non-cancer dataset may be used to search for homozygous individuals, but cannot establish heterozygous healthy individuals because phenotype information is limited. The non-cancer gnomAD v2.1 exome record shows 0 homozygotes, so the homozygous path is not met. No qualifying healthy-individual phenotype records or point totals are available, and the observed heterozygous allele count cannot satisfy the VCEP's healthy-individual path. Therefore BS2 is not met. The exact variant notations c.2204C>T, p.Ala735Val, and p.A735V were searched in APC_specifications_supplementary-material_V2.pdf.txt and no variant-specific table entry was found; this does not indicate absence of population evidence.

VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. ... The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals.
Evidence considered
  • APC VCEP BS2 modification: the non-cancer gnomAD v2.1.1 dataset cannot be used for heterozygous healthy individuals because of limited phenotype information, but can be used to search for homozygous individuals.
  • gnomAD v2.1 non-cancer exomes for APC c.2204C>T (p.Ala735Val; p.A735V): homozygotes 0; allele count 14/235764.
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt after searching all three notations; this is a reference-file search gap, not evidence absence.
  • No qualifying healthy-individual phenotype records with VCEP-defined age, colonoscopy, and phenotype information are available in the reviewed case evidence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗gnomad_v2 ↗
BP5 VCEPNot met: the reported trans variant is pathogenic APC p.Arg332Ter, not a qualifying alternate polyposis-gene variant. Details ▾Hide ▴
Reasoning

The APC VCEP permits BP5 only when a (Likely) Pathogenic variant in another adenomatous polyposis gene is identified and a colorectal polyposis phenotype is present. PMID:23159591 reports p.Ala735Val in trans with the APC pathogenic variant p.Arg332Ter, which is a second variant in APC rather than an alternate adenomatous polyposis gene; no qualifying POLD1, POLE, MUTYH, NTHL1, MSH3, MLH1, MSH2, MSH6, or PMS2 variant is documented. Thus the required alternate genetic basis is not met.

VCEP rule
Can be used, if a (Likely) Pathogenic variant in another adenomatous polyposis gene was identified (heterozygous variants in POLD1 or POLE; biallelic variants in MUTYH, NTHL1 or MSH3; in patients with onset in childhood / adolescence: biallelic variants in MLH1, MSH2, MSH6 or PMS2). This rule is only applicable when a colorectal polyposis phenotype is present.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, BP5 row: BP5 can be used for a (Likely) Pathogenic variant in another adenomatous polyposis gene, and only when a colorectal polyposis phenotype is present; the listed alternate genes are POLD1, POLE, MUTYH, NTHL1, MSH3, MLH1, MSH2, MSH6, and PMS2.
  • Kerr et al. 2013, PMID:23159591, Table 2 and family-testing text: c.2204C>T p.Ala735Val was observed in trans with the pathogenic APC p.R332X (c.994C>T) variant once; this is not an alternate gene basis.
Still missing
  • No c.2204C>T, p.Ala735Val, or p.A735V entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.2204C>T, p.Ala735Val, or p.A735V entry was found in Table-1%262.pdf.txt.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗PMID:23159591 ↗

Not assessed · 6 · no assessment recorded

PS2 VCEPNot assessed: one reported case lacks confirmed maternity, paternity, parental phenotype, and a qualifying de novo observation. Details ▾Hide ▴
Reasoning

The APC VCEP requires de novo evidence with confirmed maternity and paternity, and its scoring additionally depends on the proband's phenotype and unaffected-parent assessment. The exact-variant report in Kerr et al. documents one occurrence of c.2204C>T/p.Ala735Val and an observation in trans with p.Arg332Ter, but supplies no confirmed parental relationships, parental colonoscopy/phenotype data, or qualifying de novo observation. PS2 therefore cannot be assessed.

VCEP rule
≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. | 2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2. | 1-1.5 de novo score. For curation of de novo score see Tables 1 and 2.
Evidence considered
  • APC VCEP PS2 rule: "≥ 4 de novo scores" for Very Strong, "2-3.5 de novo scores" for Strong, and "1-1.5 de novo score" for Moderate; de novo-score curation is directed to Tables 1 and 2.
  • APC VCEP Table 2 assigns de novo scores only when phenotype points and confirmed or unconfirmed parental relationships are established: ≥1 phenotype point gives 2 with confirmed relationships or 1 without; 0.5 phenotype point gives 1 with confirmed relationships or 0.5 without.
  • Kerr et al., Table 2 and results: c.2204C>T p.Ala735Val was observed once in 1591 APC testing cases and once in trans with pathogenic p.Arg332Ter; this is not documented as a de novo observation and does not provide parental testing or phenotype scoring.
Still missing
  • Confirmed maternity and paternity for a proband carrying c.2204C>T/p.Ala735Val.
  • Proband phenotype points under APC VCEP Table 1.
  • Parental colonoscopy, adenoma counts, age, gastrointestinal tumor history, and family-history assessment.
  • The exact variant was not found in APC_specifications_supplementary-material_V2.pdf.txt or Table-1%262.pdf.txt; these files contain governing rules and tables but no variant-specific entry.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:23159591 ↗
PS3 VCEPNot assessed: no variant-specific RNA or protein functional assay was available to satisfy the APC VCEP PS3 evidence pathways. Details ▾Hide ▴
Reasoning

The APC VCEP PS3 rule requires qualifying RNA evidence or, at supporting strength, a protein assay showing increased beta-catenin-regulated transcription activity and/or decreased beta-catenin binding. The case evidence contains no variant-specific RNA or protein functional assay for c.2204C>T (p.Ala735Val/p.A735V); the relevant paper reports detection in trans with p.Arg332Ter but no functional experiment. The missense variant is codon 735, outside the VCEP-defined beta-catenin binding domain (codons 959-2129) for the PS3 protein-assay path. No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.

VCEP rule
Applicable
Evidence considered
  • APC VCEP PS3 rule: RNA assays must demonstrate the specified transcript abnormality; the supporting protein-assay path requires increased beta-catenin-regulated transcription activity and/or decreased binding to beta-catenin.
  • The case evidence contains no variant-specific RNA or protein functional assay for NM_001127510.3:c.2204C>T (NP_001120982.1:p.(Ala735Val)).
  • Kerr et al. 2013, Table 2 and Results: c.2204C>T p.Ala735Val was observed once in trans with p.Arg332Ter; this is a segregation/phase observation, not a functional assay result.
Still missing
  • No exact-variant entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • A validated variant-specific RNA or qualifying protein functional assay with the VCEP-required readouts is unavailable.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗PMID:23159591 ↗
PS4 VCEPNot assessed: the exact variant occurred in 1 of 1591 cases, but no Table 1 phenotype points can be assigned from the available report. Details ▾Hide ▴
Reasoning

The APC VCEP defines PS4 using phenotype points curated from Table 1, with 1 point for a phenotype highly specific for APC and 0.5 points for a phenotype consistent with APC but not highly specific; the strength mapping is 1-1.5 supporting, 2-3.5 moderate, 4-15.5 strong, and ≥16 very strong. PMID:23159591 reports NM_000038.6:c.2204C>T p.Ala735Val in 1 of 1591 APC testing cases and lists it as likely benign, but the extracted variant-specific report does not provide the proband's APC phenotype or enough clinical detail to assign a Table 1 phenotype point. Therefore PS4 cannot be evaluated without phenotype data, despite the exact variant being present in a clinical testing cohort.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PS4 row: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls"; the VCEP points to Fortuno et al. 2020 (PMID:33300245) for its modification.
  • Table-1%262.pdf, Table 1: phenotype point per proband is 1 for a phenotype highly specific for APC and 0.5 for a phenotype consistent with APC but not highly specific; Table 2 is for PS2/PM6 de novo scoring.
  • Kerr et al. 2013, PMID:23159591, Table 2 row: c.2204C>T p.Ala735Val, 15, pt, 1, 0.0003; the paper states the variant was seen in trans with p.R332X once, but does not provide the affected proband's Table 1 phenotype details.
Still missing
  • No c.2204C>T, p.Ala735Val, or p.A735V entry was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No c.2204C>T, p.Ala735Val, or p.A735V entry was found in Table-1%262.pdf.txt.
  • The PMID:23159591 variant report does not provide the proband phenotype needed to score Table 1 phenotype points.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:23159591 ↗
PM6 VCEPNot assessed: the single reported occurrence has no documented assumed-de-novo status, parental relationship status, or phenotype-point score. Details ▾Hide ▴
Reasoning

The APC VCEP PM6 pathway requires assumed de novo status without confirmed maternity and paternity, with de novo strength determined from phenotype points and whether parental relationships are confirmed. The exact-variant literature documents one occurrence and an observation in trans with p.Arg332Ter, but does not document an assumed-de novo proband, parental testing status, parental phenotype assessment, or the proband's APC phenotype points. PM6 cannot be assessed.

VCEP rule
2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2. | 1-1.5 de novo scores. For curation of de novo score see Tables 1 and 2. | 0.5 de novo scores. For curation of de novo score see Tables 1 and 2.
Evidence considered
  • APC VCEP PM6 rule: 2-3.5 de novo scores supports Strong, 1-1.5 de novo scores supports Moderate, and 0.5 de novo scores supports Supporting; de novo-score curation is directed to Tables 1 and 2.
  • APC VCEP Table 2 requires a phenotype point per proband and distinguishes de novo scores with confirmed versus unconfirmed parental relationships.
  • Kerr et al. reports c.2204C>T p.Ala735Val once in an APC testing cohort and once in trans with pathogenic p.Arg332Ter, without reporting assumed-de-novo status, parental relationships, or APC phenotype points.
Still missing
  • Documentation that the proband's c.2204C>T/p.Ala735Val variant was assumed de novo.
  • Whether maternity and paternity were confirmed or unconfirmed.
  • Proband phenotype points and parental unaffected assessment under APC VCEP Tables 1 and 2.
  • The exact variant was not found in APC_specifications_supplementary-material_V2.pdf.txt or Table-1%262.pdf.txt; these files contain governing rules and tables but no variant-specific entry.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:23159591 ↗
PP1 VCEPNot assessed: no qualifying affected relatives, phenotype points, or segregation meioses are reported for c.2204C>T/p.Ala735Val. Details ▾Hide ▴
Reasoning

The APC VCEP requires genotype-positive, phenotype-positive affected individuals or obligate carriers with phenotype, with at least 0.5 phenotype point for affected individuals; strength is then based on 3-4 meioses for Supporting, 5-6 for Moderate, or at least 7 meioses in at least 2 families for Strong. The exact-variant report describes one observation in trans with p.Arg332Ter, but provides no affected relatives, qualifying phenotype points, segregation across relatives, or meioses. PP1 cannot be assessed.

VCEP rule
Variant segregates in ≥ 7 meioses in ≥ 2 families. | Variant segregates in 5-6 meioses in ≥ 1 family. | Variant segregates in 3-4 meioses in ≥ 1 family.
Evidence considered
  • APC VCEP PP1 rule: Supporting requires segregation in 3-4 meioses in at least 1 family; Moderate requires 5-6 meioses in at least 1 family; Strong requires at least 7 meioses in at least 2 families.
  • APC VCEP specifies that affected individuals must exhibit at least 0.5 phenotype point, and only genotype- and phenotype-positive individuals and obligate carriers with phenotype are counted.
  • Kerr et al. reports one c.2204C>T p.Ala735Val observation in trans with p.Arg332Ter, but does not report family segregation, affected relatives, phenotype points, or meioses; the trans observation is not PP1 evidence.
Still missing
  • Genotypes and APC phenotype assessments for affected relatives or obligate carriers.
  • Number of qualifying segregation meioses and number of families.
  • The exact variant was not found in APC_specifications_supplementary-material_V2.pdf.txt or Table-1%262.pdf.txt; these files contain governing rules and tables but no variant-specific entry.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:23159591 ↗
BS4 VCEPNot assessed: no affected member lacking c.2204C>T/p.Ala735Val has a documented APC phenotype-point score. Details ▾Hide ▴
Reasoning

The APC VCEP BS4 rule requires an affected member without the variant who meets at least 1 phenotype point, or two affected members without the variant who each meet at least 0.5 phenotype points for Strong; Supporting requires one such affected member with at least 0.5 phenotype point. The available exact-variant report documents a variant observed in trans with p.Arg332Ter, but does not identify an affected relative without c.2204C>T/p.Ala735Val or provide phenotype scoring. BS4 cannot be assessed.

VCEP rule
Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see Table 1). | Affected member without the variant must score at least 0.5 phenotype points (see Table 1).
Evidence considered
  • APC VCEP BS4 rule: Strong requires 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 phenotype points; Supporting requires an affected member without the variant scoring at least 0.5 phenotype point.
  • APC VCEP Table 1 defines the phenotype-point system used for BS4.
  • Kerr et al. reports c.2204C>T p.Ala735Val in trans with p.Arg332Ter, but does not report an affected member without the variant or a BS4 phenotype-point assessment.
Still missing
  • An affected family member without c.2204C>T/p.Ala735Val.
  • That member's phenotype score under APC VCEP Table 1, or two such members each scoring at least 0.5.
  • The exact variant was not found in APC_specifications_supplementary-material_V2.pdf.txt or Table-1%262.pdf.txt; these files contain governing rules and tables but no variant-specific entry.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗vcep_table_1_262 ↗PMID:23159591 ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2204C>T is a missense SNV producing p.Ala735Val, whereas the VCEP PVS1 rule applies only to defined null-variant classes. Details ▾Hide ▴
Reasoning

APC c.2204C>T (p.Ala735Val/p.A735V) is a missense SNV in exon 17 of NM_001127510.3, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The APC VCEP PVS1 rule is limited to null variants, and the APC PVS1 decision tree contains no entry for c.2204C>T, p.Ala735Val, or p.A735V. Therefore PVS1 is not applicable; no NMD, exon-importance, or protein-length-loss assessment can convert this missense variant into a PVS1-eligible null variant.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease
Evidence considered
  • Variant assessment: NM_001127510.3:c.2204C>T is a missense consequence in exon 17, encoding NP_001120982.1:p.(Ala735Val)/p.(A735V), with no canonical splice-consensus involvement.
  • APC_specifications_supplementary-material_V2.pdf, PVS1 row: the original criterion is limited to a null variant, and the APC VCEP describes APC LOF as the predominant disease mechanism.
  • Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf, Figure 1(A): the listed PVS1 paths cover nonsense/frameshift, specified splice variants, deletions, duplications, and initiation-codon variants; the queried missense SNV is not listed.
  • Kerr et al. 2013, Table 2 and Results: APC c.2204C>T is reported as p.Ala735Val, confirming the queried variant as a missense substitution.
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf.txt.
  • No variant-specific entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
pvs1_variant_assessmentvcep_apc_specifications_supplementary_material_v2 ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 ↗PMID:23159591 ↗
PS1 N/ANot applicable: APC VCEP missense PS1 is restricted to residues 1026 and 1028, whereas this variant changes residue 735. Details ▾Hide ▴
Reasoning

The APC VCEP limits missense PS1_Moderate use to residues 1026 and 1028, represented by c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). The assessed missense variant is c.2204C>T p.(Ala735Val), outside those residues. The governing APC supplementary file contained no entry for c.2204C>T, p.Ala735Val, or p.A735V.

VCEP rule
Based on the current knowledge there are only two amino acid positions (1026 and 1028), where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) , located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). Thus, PS1_Moderate can currently only be used for missense variants at these two amino acid positions.
Evidence considered
  • APC VCEP CSPEC PP1/PS1-related criterion entries identify the missense variant as NP_001120982.1:p.(Ala735Val), residue 735.
  • APC_specifications_supplementary-material_V2.pdf, PS1 row: the only currently usable APC missense positions are 1026 and 1028, and PS1_Moderate can currently only be used at those two positions.
  • The assessed variant is c.2204C>T p.(Ala735Val), not one of the VCEP-listed positions c.3077A>G p.(Asn1026Ser) or c.3084T>A p.(Ser1028Arg).
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM1 VCEPNot applicable: APC VCEP identifies no established pathogenic missense hotspot or approved critical-domain entry covering residue 735. Details ▾Hide ▴
Reasoning

The APC CSPEC marks PM1 as not applicable, and the APC VCEP supplementary text states that residues 1026 and 1028 are not sufficiently established as a mutational hotspot and that no other pathogenic missense germline hotspots are known in APC. vcep_materials.json has an empty domain_tables object, so there is no authoritative APC approved critical-domain entry to apply to residue 735. The governing APC supplementary file contained no entry for c.2204C>T, p.Ala735Val, or p.A735V.

VCEP rule
Based on our knowledge there are only two amino acid positions (1026 and 1028), where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) (for details see PS1). However, until now there is not enough evidence to define this as a mutational hotspot. There are no other known mutational hotspots for pathogenic missense germline variants in APC.
Evidence considered
  • APC VCEP CSPEC marks PM1 as Not Applicable.
  • APC_specifications_supplementary-material_V2.pdf, PM1 row: the VCEP states that residues 1026 and 1028 are not sufficiently supported as a mutational hotspot and that there are no other known mutational hotspots for pathogenic missense germline variants in APC.
  • vcep_materials.json domain_tables is {} and therefore contains no approved APC critical functional domain list covering residue 735.
  • The case evidence reports no statistically significant hotspot for APC A735.
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • The authoritative vcep_materials.json domain_tables object is empty for APC.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM3 VCEPNot applicable: the APC VCEP excludes PM3 because familial adenomatous polyposis has autosomal dominant inheritance. Details ▾Hide ▴
Reasoning

The APC VCEP marks PM3 not applicable because familial adenomatous polyposis is an autosomal dominant disorder; therefore, recessive trans-phase evidence cannot be used for this APC variant.

VCEP rule
Not used as FAP has an autosomal dominant mode of inheritance.
Evidence considered
  • APC VCEP supplementary-material PM3 entry: "Not used as FAP has an autosomal dominant inheritance."
  • The VCEP's CSPEC entry labels PM3 applicability as "Not Applicable".
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PM4 VCEPNot applicable: the APC VCEP states PM4 is not used, and this missense substitution causes no protein-length change. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that PM4 is not used due to limited available data. The queried variant is also a missense substitution with no protein-length change, so it does not meet the original PM4 variant description of an in-frame insertion/deletion or stop-loss variant.

VCEP rule
Not used due to limited available data.
Evidence considered
  • Variant assessment identifies c.2204C>T as a missense SNV encoding p.Ala735Val, not an in-frame insertion/deletion or stop-loss variant.
  • APC_specifications_supplementary-material_V2.pdf, PM4 row: "Not used due to limited available data."
Still missing
  • No variant-specific entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
pvs1_variant_assessmentvcep_apc_specifications_supplementary_material_v2 ↗
PM5 N/ANot applicable: APC VCEP PM5 is restricted to residues 1026 and 1028, but p.Ala735Val affects residue 735. Details ▾Hide ▴
Reasoning

The APC VCEP limits PM5 to missense variants at residues 1026 and 1028, where the two listed missense variants are classified as Likely Pathogenic under APC-specific criteria. The assessed missense variant is at residue 735, so the VCEP PM5 rule does not apply. The PM5 candidate artifact found zero same-residue candidates, and the governing APC supplementary file contained no entry for c.2204C>T, p.Ala735Val, or p.A735V.

VCEP rule
Based on the current knowledge this criterion can only be used for missense variants at the two amino acid positions 1026 and 1028, where reported missense variants can be classified as Likely Pathogenic based on the APC-specific criteria (c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg)) (for details see PS1).
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PM5 row: PM5 can only be used for missense variants at amino acid positions 1026 and 1028, represented by c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg).
  • The assessed variant is NM_001127510.3:c.2204C>T, NP_001120982.1:p.(Ala735Val), residue 735.
  • pm5_candidates.json reports same_residue_candidates = 0 and no candidates.
Still missing
  • No entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
  • No same-residue comparator was available in pm5_candidates.json.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
PP4 VCEPNot applicable: the APC VCEP states PP4 is captured by PS4 and cannot be used independently. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that PP4 is already captured by the PS4 specifications and cannot be used as independent evidence.

VCEP rule
Already captured by the specifications of PS4, and thus cannot be used as independent evidence.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PP4 row: "Already captured by the specifications of PS4, and thus cannot be used as independent evidence."
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
PP5 VCEPNot applicable: the APC VCEP does not use PP5 without the primary evidence underlying an expert opinion. Details ▾Hide ▴
Reasoning

The APC VCEP does not use PP5, stating that expert opinions should only be considered when accompanied by the primary evidence used.

VCEP rule
Not used as recommended by Biesecker et al. 2018 (PMID: 29543229): Expert opinions should only be considered if accompanied by the primary evidence used.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, PP5 row: the criterion is not used as recommended by Biesecker et al. 2018 because expert opinions should be accompanied by the primary evidence used.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BS3 N/ANot applicable: p.Ala735Val is a missense variant at codon 735, outside the VCEP BS3 protein-assay domain of codons 959-2129. Details ▾Hide ▴
Reasoning

The APC VCEP BS3 supporting protein-assay path is restricted to variants within the beta-catenin binding domain at codons 959-2129, whereas p.Ala735Val is at codon 735. The alternative BS3 RNA-assay paths are restricted to synonymous or intronic variants, while this variant is missense. Therefore the variant lies outside every BS3 assay path named by the VCEP.

VCEP rule
**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition **OR** **Protein assay** show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of _APC_, see PMID: 33348689)
Evidence considered
  • APC VCEP BS3 supporting rule restricts the protein-assay path to retention of beta-catenin-regulated transcription activity comparable to wild-type for variants within APC codons 959-2129.
  • Variant normalization identifies NP_001120982.1:p.(Ala735Val)/p.(A735V), placing the missense change at codon 735; the VCEP BS3 RNA paths apply to synonymous or intronic variants, not this missense variant.
Still missing
  • No exact-variant entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP3 VCEPNot applicable: the APC VCEP states BP3 is not used, and c.2204C>T is a missense SNV rather than an in-frame indel. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP3 is not used due to limited available data. The queried variant is a missense SNV rather than an in-frame deletion or insertion in a repeat region, so BP3 has no applicable VCEP path.

VCEP rule
APC VCEP: Not used due to limited available data.
Evidence considered
  • Variant assessment identifies c.2204C>T as a missense SNV encoding p.Ala735Val, not an in-frame insertion/deletion.
  • APC_specifications_supplementary-material_V2.pdf, BP3 row: "APC VCEP: Not used due to limited available data."
Still missing
  • No variant-specific entry for c.2204C>T, p.Ala735Val, or p.A735V was found in APC_specifications_supplementary-material_V2.pdf.txt.
Sources
pvs1_variant_assessmentvcep_apc_specifications_supplementary_material_v2 ↗
BP4 N/ANot applicable: APC BP4 explicitly excludes missense variants, and c.2204C>T produces the missense change p.Ala735Val. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP4 is not applicable to missense variants. This variant is a missense SNV, NM_001127510.3:c.2204C>T (NP_001120982.1:p.(Ala735Val)); therefore, no splice prediction can activate BP4 for this variant. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
**Missense variants:** BP4 is not applicable. **Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Evidence considered
  • APC VCEP BP4 rule, cspec BP4 entry: missense variants are not applicable; only synonymous or intronic variants use multiple in silico splicing predictors for no impact.
  • Variant normalization: NM_001127510.3:c.2204C>T is a missense SNV producing NP_001120982.1:p.(Ala735Val).
  • APC_specifications_supplementary-material_V2.pdf, BP4 row: BP4 is not applicable to missense variants.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP6 VCEPNot applicable: the APC VCEP does not use BP6 for unsupported expert reports of benignity. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP6 is not used as recommended by Biesecker et al. 2018 because expert opinions should be accompanied by the primary evidence used.

VCEP rule
Not used as recommended by Biesecker et al. 2018 (PMID: 29543229): Expert opinions should only be considered if accompanied by the primary evidence used.
Evidence considered
  • APC_specifications_supplementary-material_V2.pdf, BP6 row: the criterion is not used as recommended by Biesecker et al. 2018 because expert opinions should be accompanied by the primary evidence used.
Sources
vcep_apc_specifications_supplementary_material_v2 ↗
BP7 N/ANot applicable: BP7 covers only synonymous or intronic variants at or beyond +7/-21, while c.2204C>T is an exonic missense variant. Details ▾Hide ▴
Reasoning

The APC VCEP restricts BP7 to synonymous variants or intronic variants at or beyond +7/-21. This variant is exonic and missense at exon 17, c.2204C>T (p.Ala735Val), so BP7 is outside its governing scope regardless of the SpliceAI result. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
  • APC VCEP BP7 rule, cspec BP7 entry: BP7 requires a synonymous or intronic variant at or beyond +7/-21 and multiple splicing prediction algorithms predicting no splice impact.
  • Variant facts: NM_001127510.3:c.2204C>T is located in exon 17 and produces the missense protein change NP_001120982.1:p.(Ala735Val).
  • APC_specifications_supplementary-material_V2.pdf, BP7 row: the criterion is limited to synonymous or intronic variants at or beyond +7/-21.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Identifiers

Gene
APC
Transcript
NM_001127510.3
Coding (HGVS c.)
NM_001127510.3:c.2204C>T
Protein (HGVS p.)
NP_001120982.1:p.(Ala735Val)
GRCh38
chr5:112837798 C>T
GRCh37
chr5:112173495 C>T
Location and type
Exon 17 · missense
ClinVar
3226012, 646268, 41521
COSMIC
COSV57326152

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 v4.1 115 / 1,613,948 alleles AF 7.13e-05 · 0 homozygotes · FAF 0.000187
gnomAD v2.1 17 / 281,382 alleles AF 6.04e-05 · 0 homozygotes · FAF 4.43e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 7.1e-05 · 115 / 1,613,948 alleles · 0 hom · FAF 0.00019
African/African American21 / 75,014 0.00028
Remaining individuals8 / 62,496 0.00013
East Asian5 / 44,868 0.00011
European (non-Finnish)81 / 1,180,014 6.9e-05
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 6e-05 · 17 / 281,382 alleles · 0 hom · FAF 4.4e-05
East Asian4 / 19,896 0.0002
European (non-Finnish)11 / 128,062 8.6e-05
African/African American2 / 24,888 8e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 7.12538e-05; MAF= 0.00713%, 115/1613948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000279948; MAF= 0.02799%, 21/75014 alleles, homozygotes = 0); grpmax FAF= 0.00018731.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.04161e-05; MAF= 0.00604%, 17/281382 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000201045; MAF= 0.02010%, 4/19896 alleles, homozygotes = 0); grpmax FAF= 4.426e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.001086130118388183, 20/18414 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -245 bp
0.000
SpliceAI acceptor gainat +285 bp
0.000
SpliceAI donor lossat +225 bp
0.000
SpliceAI donor gainat -176 bp
0.000
Pangolin splice lossmagnitude shown
-0.007
Pangolin splice gain
0.002

Other predictors

REVEL
0.250
BayesDel
-0.096

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta 0.00 predicts no significant splice impact, whereas APC missense PP3 requires splicing evidence revealing a possible effect. Details ▾Hide ▴
Reasoning

The APC VCEP limits PP3 for missense variants to in silico splicing prediction used to reveal a possible splicing effect; it does not permit conservation or other protein-impact predictors on this path. The available SpliceAI result predicts no significant splice impact, with a maximum delta score of 0.00, so the missense-specific PP3 path is not supported. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
**Missense variants:** Do not use computational prediction models for conservation, evolution, etc. _In silico_ splicing predictors should be used for presumed missense variants to reveal possible splicing effects. **Non-canonical splicing variants:** Multiple _in silico_ splicing predictors support a deleterious effect.
Evidence considered
  • APC VCEP PP3 rule, cspec PP3 entry: for missense variants, do not use conservation/evolution computational prediction models; use in silico splicing predictors to reveal possible splicing effects.
  • SpliceAI Lookup for NM_001127510.3:c.2204C>T: max delta score 0.00; the case evidence states that SpliceAI predicts no significant splice impact.
  • APC_specifications_supplementary-material_V2.pdf, PP3 row: the APC VCEP-specific missense path is limited to in silico splicing prediction.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗spliceai ↗
BP4 N/ANot applicable: APC BP4 explicitly excludes missense variants, and c.2204C>T produces the missense change p.Ala735Val. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly states that BP4 is not applicable to missense variants. This variant is a missense SNV, NM_001127510.3:c.2204C>T (NP_001120982.1:p.(Ala735Val)); therefore, no splice prediction can activate BP4 for this variant. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
**Missense variants:** BP4 is not applicable. **Synonymous (silent) or intronic variants**: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Evidence considered
  • APC VCEP BP4 rule, cspec BP4 entry: missense variants are not applicable; only synonymous or intronic variants use multiple in silico splicing predictors for no impact.
  • Variant normalization: NM_001127510.3:c.2204C>T is a missense SNV producing NP_001120982.1:p.(Ala735Val).
  • APC_specifications_supplementary-material_V2.pdf, BP4 row: BP4 is not applicable to missense variants.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗
BP7 N/ANot applicable: BP7 covers only synonymous or intronic variants at or beyond +7/-21, while c.2204C>T is an exonic missense variant. Details ▾Hide ▴
Reasoning

The APC VCEP restricts BP7 to synonymous variants or intronic variants at or beyond +7/-21. This variant is exonic and missense at exon 17, c.2204C>T (p.Ala735Val), so BP7 is outside its governing scope regardless of the SpliceAI result. The APC VCEP supplementary full-text file was searched for c.2204C>T, p.Ala735Val, and p.A735V, with no variant-specific entry found.

VCEP rule
A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
  • APC VCEP BP7 rule, cspec BP7 entry: BP7 requires a synonymous or intronic variant at or beyond +7/-21 and multiple splicing prediction algorithms predicting no splice impact.
  • Variant facts: NM_001127510.3:c.2204C>T is located in exon 17 and produces the missense protein change NP_001120982.1:p.(Ala735Val).
  • APC_specifications_supplementary-material_V2.pdf, BP7 row: the criterion is limited to synonymous or intronic variants at or beyond +7/-21.
Still missing
  • APC_specifications_supplementary-material_V2.pdf.txt was searched for c.2204C>T, p.Ala735Val, and p.A735V; no variant-specific entry was found.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2 ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.25. BayesDel score = -0.0955743.

8 paper records listed. 1 cited in the classification.

Cited in the classification

  • APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests.
    Kerr SE et al. · 2013 Jan
    The paper reports APC c.2204C>T as p.Ala735Val in its likely benign variant table, confirming that the queried change is a missense substitution; it provides no protein-length-change or repeat-region indel evidence for this variant.
    → BP1 · supporting → BP2 · supporting Names this variant
    PMID 23159591 ↗
    Source detail
    c.2204C>T p.Ala735Val 15 pt 1 0.0003 This study

    Location Table 2, likely benign APC variants

    Context Retrospective review of 1591 consecutive cases submitted for full APC gene analysis from 2006 through 2009; sequencing and targeted family testing were performed.

Other recorded publications

  • Clinical utility gene card for: familial adenomatous polyposis (FAP) and attenua
    No paper-specific finding is recorded.
    PMID 21368914 ↗
  • Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.
    Johnston JJ et al. · 2012
    No paper-specific finding is recorded.
    PMID 22703879 ↗
  • Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.
    Tung N et al. · 2015
    No paper-specific finding is recorded.
    PMID 25186627 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Cl
    No paper-specific finding is recorded.
    PMID 25452455 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint co
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
    Yurgelun MB et al. · 2015
    No paper-specific finding is recorded.
    PMID 25980754 ↗

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

gnomAD v4.1 115 / 1,613,948 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 7 Likely benign · 3 Benign · 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 7.12538e-05; MAF= 0.00713%, 115/1613948 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000279948; MAF= 0.02799%, 21/75014 alleles, homozygotes = 0); grpmax FAF= 0.00018731.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 6.04161e-05; MAF= 0.00604%, 17/281382 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000201045; MAF= 0.02010%, 4/19896 alleles, homozygotes = 0); grpmax FAF= 4.426e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.001086130118388183, 20/18414 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory). (ClinVarID = 41521)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.25. BayesDel score = -0.0955743.

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; COSV57326152, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.