Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Benign.A 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.
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.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
Met (stand-alone): gnomAD East Asian popmax allele frequency 0.823% (v2.1) and 0.379% (v4.1) exceeds the >=0.1% BA1 threshold by 3- to 8-fold.
BS1Strong
BS1 · strong
Met (strong): the same East Asian popmax frequencies (0.823% v2.1, 0.379% v4.1) exceed the >=0.001% BS1 threshold by several hundred-fold. Same observation as BA1, so not independent evidence.
Recorded classification: Benign
Benign: under the InSiGHT APC VCEP v2.1 Rule 26 stand-alone rule, BA1 is met (East Asian popmax AF 0.823% v2.1 / 0.379% v4.1, >=3-fold above the 0.1% threshold), and no pathogenic criterion is met.
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
211 / 1,613,984 alleles
gnomAD v4.1: 211 / 1,613,984 alleles. Recorded AF 0.000130732. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000599257; MAF= 0.05993%, 169/282016 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00823211; MAF= 0.82321%, 164/19922 alleles, homozygotes = 1); grpmax FAF= 0.00700099.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009231103388357949, 17/18416 alleles, homozygotes = 0).
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.
ACMG/AMP criteria under ClinGen APC VCEP v2.1, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
NM_001127510.3:c.3374T>C is a single-nucleotide substitution producing NP_001120982.1:p.(Val1125Ala) - a missense amino-acid substitution (VEP most_severe_consequence 'missense_variant'), with SpliceAI max delta score 0.00 indicating no predicted splice impact.
The governing framework is the ClinGen InSiGHT APC VCEP v2.1 specification (framework_mode 'vcep'). Under it, PVS1 is routed through the APC-specific Figure 1 decision tree for null variants; PM4 is declared not used (limited available data) and BP3 is declared Not Applicable, so generic ACMG defaults are not invoked for PM4/BP3.
All three adjudicated criteria (PVS1, PM4, BP3) target loss-of-function null alleles (nonsense/frameshift/canonical splice) or protein-length-changing alleles (in-frame indel, duplication, stop-loss); a missense SNV with unchanged protein length and no splice impact falls outside the scope of each, so all are not applicable and no consequence-based pathogenic/benign contribution is made by this group.
No evidence gap remains: the consequence class (missense SNV) is well established by normalization/VEP data and corroborated by primary literature (PMID:16569251, PMID:18199528), and the VCEP applicability declarations for PM4/BP3 are explicit.
PS4 not met: the only case-control data for APC c.3374T>C (p.V1125A), PMID:16569251, show no significant enrichment (3/80 CRC patients vs 1/74 controls); PMID:18199528 reports a single carrier among 691 referred patients with no control arm; the variant is not absent from controls (gnomAD v4.1 AF 0.0131% overall, 0.379% East Asian), excluding the Note-2 moderate pathway; and no index-proband phenotype was available to score VCEP Table 1 phenotype points. No pathogenic phenotype/prevalence evidence is contributed by this group.
PP4 not applicable: phenotype specificity is already captured by the APC VCEP PS4 phenotype-point specification.
PP5 and BP6 not applicable: the APC VCEP does not use these criteria, and no ClinVar expert-panel classification exists for this exact variant (0 expert-panel submissions); the aggregate Likely benign/Benign ClinVar labels are ordinary single-submitter laboratory assertions and must not trigger PP5 or BP6.
BP5 not met: no alternate genetic basis of a colorectal polyposis phenotype (e.g., biallelic MUTYH/NTHL1/MSH3, heterozygous POLD1/POLE) is documented for any carrier of this variant.
Net contribution of the phenotype_prevalence_assertions group: no criterion supporting pathogenicity (PS4/PP4/PP5) and no criterion supporting benignity (BP5/BP6); prevalence observations relevant to benign classification are handled by the population-frequency criteria group.
Governing framework is the APC InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification (cspec v2.1), which takes precedence over generic ACMG/AMP for APC.
c.3374T>C is a missense variant (p.Val1125Ala), which determines applicability of all three computational-evidence criteria in this group.
PP3: applicable but not met - the VCEP restricts PP3 for missense variants to in silico splicing predictors (generic missense computational models excluded), and SpliceAI predicts no splice impact (max delta 0.00).
BP4: not applicable - the APC VCEP BP4 rule explicitly states BP4 is not applicable to missense variants; it is reserved for synonymous/intronic variants with multiple splicing predictors suggesting no impact.
BP7: not applicable - the APC VCEP BP7 rule is restricted to synonymous (silent) or intronic variants at or beyond +7/-21; this missense exonic variant does not qualify.
SpliceAI's no-impact prediction (max delta 0.00) was evaluated once and was not double-counted across PP3, BP4, or BP7; it supports none of the three criteria under the APC specification.
No fetched publication (paper_extracts.json) contains variant-level in silico splicing or missense computational evidence for c.3374T>C / p.Val1125A; literature_pass.json indexes no papers for PP3/BP4/BP7.
Population-frequency evidence for APC c.3374T>C p.(Val1125Ala) is strongly benign: gnomAD East Asian popmax AF is 0.823% (v2.1) and 0.379% (v4.1), with grpmax FAF 0.700% (v2.1) and 0.332% (v4.1) - each >= 3-fold above the APC VCEP v2.1 BA1 threshold of 0.1% (0.001).
BA1 is met at stand-alone strength. BS1 (popmax filtering AF >= 0.001%) is formally met but derives from the identical popmax observation and must not be added as independent evidence on top of BA1.
PM2 is not met: the variant is not rare in controls (overall AF 0.0131-0.0599%, East Asian 0.379-0.823%) versus the VCEP PM2 ceiling of <= 0.0003% for allele counts > 1; no supporting-strength rarity credit applies.
BS2 is not met: available evidence yields only ~0.5-1 healthy-individual point (one health-examination control, PMID:16569251) and at most one homozygote (gnomAD v2.1; zero in v4.1 and gnomAD-Canada), below the >= 3 points / >= 2 homozygotes required even for supporting strength.
The high East Asian frequency is corroborated across gnomAD v2.1, gnomAD v4.1, gnomAD-Canada, and a Taiwanese case-control study (PMID:16569251), supporting a genuine polymorphism rather than a technical or threshold artifact.
No criteria match.
Met · 2
BA1Stand aloneMet (stand-alone): gnomAD East Asian popmax allele frequency 0.823% (v2.1) and 0.379% (v4.1) exceeds the >=0.1% BA1 threshold by 3- to 8-fold.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen InSiGHT HCRC/Polyposis VCEP APC v2.1 specification (cspec found; framework_mode=vcep), which defines BA1 (Stand Alone) as met when the gnomAD popmax filtering allele frequency (AF) is >= 0.1% (0.001). The variant NM_001127510.3:c.3374T>C p.(Val1125Ala) (rs377278397) is present in gnomAD v2.1 at an East Asian popmax AF of 0.00823 (0.823%; 164/19,922 alleles) with exome grpmax FAF 0.00700 (0.700%), and in gnomAD v4.1 at an East Asian popmax AF of 0.00379 (0.379%; 170/44,878 alleles) with joint grpmax FAF 0.00332 (0.332%); gnomAD-Canada shows a concordant East Asian AF of 0.01196 (1.196%). Both gnomAD versions therefore exceed the 0.1% BA1 threshold by >= 3-fold (using the more conservative v4.1 grpmax FAF) to >= 7-fold (v2.1), under either the popmax AF or the filtering-AF reading of the rule. Consistency across gnomAD v2.1, v4.1, and gnomAD-Canada, presence of a homozygote in v2.1, and concordant frequencies in an East Asian case-control study indicate a genuine East Asian polymorphism rather than a threshold/sequencing artifact. BA1 is met at stand-alone strength. Note: the VCEP instruction recommends the gnomAD v2.1.1 non-cancer dataset, which was not captured separately in this case; the AF margins are so large that this does not affect the call.
Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001).
Evidence considered
APC VCEP v2.1 (cspec): BA1 rule states 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001)' at Stand Alone strength; instructions recommend the non-cancer dataset from gnomAD v2.1.1.
gnomad_v2 (gnomAD v2.1, GRCh37 5-112174665-T-C): overall AF 0.000599 (0.0599%; 169/282,016 alleles, 1 homozygote); East Asian popmax AF 0.00823 (0.823%; 164/19,922 alleles, 1 homozygote); exome grpmax FAF 0.00700 (0.700%).
gnomad_v4 (gnomAD v4.1, GRCh38 5-112838968-T-C): overall AF 0.000131 (0.0131%; 211/1,613,984 alleles, 0 homozygotes); East Asian popmax AF 0.00379 (0.379%; 170/44,878 alleles); joint grpmax FAF 0.00332 (0.332%).
gnomad_canada (gnomAD-Canada v1.0): overall AF 0.000923 (0.0923%; 17/18,416 alleles, 0 homozygotes); East Asian AF 0.01196 (1.196%; 16/1,338 alleles).
East Asian popmax AF (0.823% v2.1; 0.379% v4.1) and grpmax FAF (0.700% v2.1; 0.332% v4.1) both exceed the VCEP BA1 threshold of 0.1% in two independent gnomAD releases plus gnomAD-Canada, giving >= 3-fold margin under the most conservative metric; the v2.1 homozygote and cross-dataset concordance argue the high East Asian frequency is a real population polymorphism (rs377278397), not an artifact.
BS1StrongMet (strong): the same East Asian popmax frequencies (0.823% v2.1, 0.379% v4.1) exceed the >=0.001% BS1 threshold by several hundred-fold. Same observation as BA1, so not independent evidence.
Details ▾Hide ▴
Reasoning
APC VCEP v2.1 defines BS1 (Benign Strong) as met when gnomAD popmax filtering AF >= 0.001% (0.00001). The same gnomAD observations used for BA1 satisfy this lower threshold: East Asian popmax AF 0.823% (v2.1) and 0.379% (v4.1), grpmax FAF 0.700% (v2.1) and 0.332% (v4.1), all several orders of magnitude above 0.001%. BS1 is therefore formally met at strong strength. IMPORTANT for later combination: BS1 rests on the exact same single population observation that already met BA1 (nested thresholds); it must not be counted as independent evidence in addition to BA1. Reporting is for completeness of the per-criterion adjudication.
Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001).
Evidence considered
APC VCEP v2.1 (cspec): BS1 rule states 'GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001)' at Benign Strong strength; instructions recommend the non-cancer dataset from gnomAD v2.1.1.
gnomad_v2: East Asian popmax AF 0.00823 (0.823%) and exome grpmax FAF 0.00700 (0.700%), far above the 0.001% BS1 threshold.
gnomad_v4: East Asian popmax AF 0.00379 (0.379%) and joint grpmax FAF 0.00332 (0.332%), far above the 0.001% BS1 threshold.
gnomad_canada: East Asian AF 0.01196 (1.196%), corroborating the East Asian excess.
BS1 and BA1 thresholds are nested; this criterion is met only because the same popmax frequency that triggered BA1 also exceeds the lower BS1 cutoff, so it is not an independent line of evidence.
PS4Not met: no case-control enrichment - p.V1125A occurred in 3 of 80 Taiwanese CRC patients versus 1 of 74 controls, a non-significant difference.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen InSiGHT APC VCEP v2.1 (cspec): PS4 is Applicable and is scored either by the Table 1 phenotype-point system per proband (1-1.5 points = Supporting up to >=16 = Very Strong) or by case-control enrichment (OR/RR >5 with CI excluding 1; Note 2 allows Moderate for very rare variants seen in multiple unrelated patients and absent in controls). No case-control enrichment exists for c.3374T>C: PMID:16569251 (Taiwanese case-control, 80 CRC patients vs 74 healthy adults, full APC ORF sequenced) found p.V1125A in 3 patients vs 1 control and states the prevalence did not differ significantly between groups. PMID:18199528 (691 patients referred for FAP/multiple polyps testing) observed V1125A in a single non-FAP/non-MAP patient with 11-99 colorectal adenomas, a case series with no control arm and no replication in multiple unrelated patients. The PS4 Note 2 moderate pathway is precluded because the variant is not absent from controls: gnomAD v4.1 overall AF 0.0131% (211/1,613,984) with East Asian AF 0.379% (170/44,878) and one gnomAD v2.1 homozygote. The bundle contains no index-proband phenotype description, so the Table 1 phenotype-point pathway could not be scored directly (0 points scored from available materials); a highly APC-specific proband phenotype would require re-evaluation. PS4 therefore is not met on all scorable evidence.
Evidence considered
cspec (ClinGen InSiGHT APC VCEP v2.1): PS4 Applicable; Very Strong >=16 phenotype points, Strong 4-15.5, Moderate 2-3.5, Supporting 1-1.5 points per Table 1; original ACMG summary retains case-control enrichment (RR/OR >5, CI excluding 1) with Note 2 permitting Moderate for very rare variants in multiple unrelated patients absent from controls.
PMID:16569251: case-control study of 80 Taiwanese colorectal cancer patients vs 74 healthy adults with the entire APC coding region screened; p.V1125A (g.3374T>C) was found in 3 patients and 1 control and the authors state its prevalence did not differ significantly between groups - direct evidence against PS4 enrichment.
PMID:18199528: V1125A listed in Table 1 among 61 rare (MAF <2%) inherited nonsynonymous APC variants, identified in a single non-FAP non-MAP patient with 11-99 colorectal adenomas out of 691 referred patients; case series without control arm, insufficient for enrichment and inconsistent with the multiple-unrelated-patients requirement of PS4 Note 2.
gnomad_v4: variant present in 211/1,613,984 alleles (AF 0.0131% overall; East Asian AF 0.379%, 170/44,878 alleles) - not absent from population controls, precluding the PS4 Note 2 moderate pathway.
gnomad_v2: variant present at AF 0.0599% overall with East Asian AF 0.823% (164/19,922) and 1 homozygote - consistent with absence of pathogenic enrichment in affected cohorts.
No phenotype-point features (Table 1: typical/other colorectal polyposis, desmoids, WNT medulloblastoma, hepatoblastoma, CHRPE, gastric/duodenal adenomas, osteomas, FAP family history) for the index case were available anywhere in the case bundle.
Still missing
No index-proband clinical phenotype (polyp counts, extracolonic features, family history) is present in the case bundle, so the VCEP Table 1 phenotype-point pathway could not be scored; if proband phenotype data become available, PS4 should be re-assessed.
Available case-control data are modest and East Asian-specific (80 cases/74 controls, PMID:16569251); larger phenotype-matched case-control or cohort data could refine this assessment.
PM2Not met: gnomAD v4.1 overall allele frequency 0.0131% is ~44-fold above the PM2 ceiling of <=0.0003%, so the variant is far from rare.
Details ▾Hide ▴
Reasoning
APC VCEP v2.1 PM2 (Supporting only) requires the variant to be rare in controls: AF <= 0.0003% (0.000003) when allele count > 1, or AF < 0.001% (0.00001) when allele count <= 1. The variant is far too common to meet this ceiling. Observed allele counts are >> 1 everywhere (AC 169 in gnomAD v2.1; AC 211 in gnomAD v4.1; AC 17 in gnomAD-Canada), so the applicable threshold is AF <= 0.0003%. Observed overall AF is 0.000599 (0.0599%) in gnomAD v2.1 and 0.000131 (0.0131%) in gnomAD v4.1 - roughly 200-fold (v2.1) to 44-fold (v4.1) above the 0.0003% ceiling - and the East Asian popmax AF (0.379-0.823%) is higher still. The variant is therefore not rare in controls and PM2 is not met; no PM2 (even at supporting strength) applies.
Rule
Rare in controls, defined by an allele frequency <= 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is <= 1.
Evidence considered
APC VCEP v2.1 (cspec): PM2 rule (Supporting strength) states 'Rare in controls, defined by an allele frequency <= 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is <= 1'; instructions recommend the total population of the non-cancer gnomAD v2.1.1 dataset.
gnomad_v2: allele count 169 (> 1), overall AF 0.000599 (0.0599%) - ~200x above the 0.0003% PM2 ceiling.
gnomad_v4: allele count 211 (> 1), overall AF 0.000131 (0.0131%) - ~44x above the 0.0003% PM2 ceiling; East Asian popmax AF 0.00379 (0.379%).
gnomad_canada: allele count 17 (> 1), AF 0.000923 (0.0923%) - far above the ceiling.
Because the observed AF exceeds the PM2 rarity ceiling by one to two orders of magnitude in every dataset, PM2 cannot be met regardless of which gnomAD release/subset is used.
PP3Not met: the APC VCEP permits only splicing predictions for missense variants, and SpliceAI reports max delta 0.00 - no predicted splicing impact.
Details ▾Hide ▴
Reasoning
Variant is a missense SNV (NM_001127510.3:c.3374T>C, p.(Val1125Ala), confirmed missense_variant by VEP/ClinVar/Mutalyzer). The governing APC InSiGHT VCEP (cspec v2.1) PP3 supporting rule states that for missense variants, computational prediction models for conservation/evolution etc. must NOT be used, and only in silico splicing predictors may be used to reveal possible splicing effects (non-canonical splice variants require multiple predictors supporting a deleterious effect). Under this specification the missense in-silico path (REVEL 0.455; BayesDel 0.3287, both retrieved by prefetch) is not usable for PP3, and BayesDel additionally has no verified published calibration threshold available to this pipeline. On the permitted splice-impact path, SpliceAI (the first of the VCEP's recommended splice predictors) reports max delta = 0.00 with DS_AG = DS_AL = DS_DG = DS_DL = 0.0, i.e., no predicted disruption of a native splice site and no predicted creation of a cryptic splice site. There is therefore no computational evidence of a deleterious splicing effect, so PP3 is not met.
Rule
APC VCEP (cspec v2.1) PP3_Supporting: Missense variants - do not use computational prediction models; in silico splicing predictors should be used to reveal possible splicing effects. Non-canonical splicing variants - multiple in silico splicing predictors support a deleterious effect.
Evidence considered
APC InSiGHT VCEP (cspec v2.1) PP3 supporting 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.
SpliceAI Lookup (source key 'spliceai') queried with NM_001127510.3:c.3374T>C (GRCh37 5-112174665-T-C): max delta score = 0.00; DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0 - no significant splice impact predicted (no native site loss, no cryptic site gain).
Prefetch retrieved missense predictor scores (REVEL 0.455, BayesDel 0.328746) but these were not applied to PP3: the APC VCEP explicitly excludes generic computational prediction models for missense variants, and BayesDel has no verified published threshold available to this pipeline.
APC VCEP PP3 does not pre-assign PP3 for this variant position in any gene-specific lookup material; no such lookup spreadsheet exists in the case's VCEP files (index.txt absent, user_files empty).
Still missing
Only SpliceAI was run for this case; MaxEntScan and VarSeak (the other splice programs the APC VCEP recommends, see PS1 instructionsToUse) were not retrieved. A positive splice-impact call from a second algorithm cannot be formally excluded, although a SpliceAI max delta of 0.00 provides no support for PP3.
BS2Not met: roughly 0.5-1 healthy-individual point (one of 74 Taiwanese controls) and a single gnomAD homozygote fall short of the >=3 points or >=2 homozygotes required.
Details ▾Hide ▴
Reasoning
APC VCEP v2.1 BS2 requires >= 10 healthy-individual points OR >= 2 homozygous observations (strong), or >= 3 points (supporting). A healthy individual earns 1 point only with documented age >= 50 years plus < 5 adenomatous polyps on colonoscopy (or CRC/polyposis not the testing indication); 0.5 points for individuals described by control/non-cancer/normal/unaffected keywords. The VCEP explicitly forbids using gnomAD non-cancer heterozygotes as healthy individuals (limited phenotype information; already used for BA1/BS1), allowing gnomAD only for homozygote searching. Available evidence: (1) gnomAD v2.1 contains a single homozygote (1 of 282,016 alleles; East Asian exome), and gnomAD v4.1 and gnomAD-Canada contain zero homozygotes - below the >= 2 homozygous observations needed; (2) in the literature set, PMID:16569251 reports the variant in 1 of 74 healthy Taiwanese health-examination controls (~0.5 point) and PMID:18199528 reports the only other carrier as an affected patient with 11-99 colorectal adenomas, contributing no healthy points. Total ~0.5-1 point, well below the >= 3 points needed for BS2_Supporting. BS2 is therefore not met.
Rule
>= 10 points for healthy individuals OR >= 2 times in homozygous state (Strong); >= 3 points for healthy individuals (Supporting). A healthy individual worth 1 point: age >= 50 years + < 5 adenomatous polyps at colonoscopy + absence of Table-1 features, OR age >= 50 years + colorectal cancer/polyposis not the indication for testing. A healthy individual worth 0.5 points: keywords including control, non-cancer, normal, unaffected population.
Evidence considered
APC VCEP v2.1 (cspec): BS2 rule requires >= 10 points (strong) or >= 3 points (supporting) for healthy individuals, or >= 2 homozygous observations (strong); instructions state the gnomAD v2.1.1 non-cancer dataset cannot be used for 'heterozygous healthy individuals' but can be used to search for homozygous individuals.
gnomad_v2: exactly 1 homozygote for 5-112174665-T-C (East Asian exome, total AC 169/282,016), below the 2-homozygote threshold.
gnomad_v4 (0 homozygotes) and gnomad_canada (0 homozygotes) corroborate that the homozygous count never reaches 2 in any dataset.
PMID:16569251: p.V1125A was found in 1 of 74 healthy adults in the health-examination (control) group of a Taiwanese case-control study - a control-keyword individual worth ~0.5 point; even crediting 1 point, the total is far below 3.
PMID:18199528: V1125A carrier was an affected patient with 11-99 colorectal adenomas (non-FAP/non-MAP), i.e., not a healthy individual; this paper supplies no BS2 points.
Still missing
No case evidence documents heterozygous carriers aged >= 50 years with < 5 adenomatous polyps at colonoscopy (or with CRC/polyposis ruled out as the testing indication), so no 1-point healthy individuals can be counted.
Only 1 homozygote (gnomAD v2.1 total; 0 in v4.1 and gnomAD-Canada) versus the >= 2 required; the VCEP-recommended gnomAD v2.1.1 non-cancer homozygote count was not separately captured.
BP5Not met: no documented pathogenic variant in another polyposis gene (e.g., biallelic MUTYH or POLD1/POLE) was found in any p.Val1125Ala carrier.
Details ▾Hide ▴
Reasoning
The ClinGen InSiGHT APC VCEP v2.1 (cspec) makes BP5 Applicable at Supporting strength but only 'for an alternate genetic basis of the colorectal polyposis phenotype' - i.e., a documented (Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous POLD1/POLE; biallelic MUTYH/NTHL1/MSH3; in childhood/adolescent-onset cases biallelic MLH1/MSH2/MSH6/PMS2) in a patient whose polyposis phenotype is present. No evidence in the case bundle documents any such alternate genetic basis: the case reports describing carriers of p.V1125A (PMID:16569251, PMID:18199528) are APC-focused studies with no reported co-occurring pathogenic variant in another polyposis gene, and no proband-level multi-gene panel result or polyposis phenotype for an index case is provided. BP5 therefore is not met.
Evidence considered
cspec (ClinGen InSiGHT APC VCEP v2.1): BP5 Applicable, Supporting strength, rule 'Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.'
vcep_apc_specifications_supplementary_material_v2 (BP5 instructions): alternate basis means heterozygous (Likely) Pathogenic POLD1/POLE, biallelic MUTYH/NTHL1/MSH3, or in childhood/adolescent-onset cases biallelic MLH1/MSH2/MSH6/PMS2, and the rule is only applicable when a colorectal polyposis phenotype is present.
PMID:16569251 and PMID:18199528 (case reports carrying p.V1125A) report no co-occurring pathogenic variant in another adenomatous polyposis gene and no alternate molecular diagnosis for any carrier.
No case-level finding in the bundle shows a colorectal polyposis phenotype attributable to an alternate genetic basis in a carrier of c.3374T>C.
Still missing
No proband-level phenotype or multi-gene polyposis panel results (MUTYH, NTHL1, MSH3, POLD1, POLE, and in early-onset cases MMR genes) were available; BP5 would only be met if an alternate (Likely) Pathogenic polyposis-gene variant were documented in a case carrying c.3374T>C.
PS1Not assessed: insufficient evidence was available to determine whether an established pathogenic variant produces the same amino-acid change.
Details ▾Hide ▴
Reasoning
PS1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PS2Not assessed: insufficient evidence was available to confirm a de novo origin.
Details ▾Hide ▴
Reasoning
PS2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PS3Not assessed: insufficient evidence was available from functional studies to judge impact on protein function.
Details ▾Hide ▴
Reasoning
PS3 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PM1Not assessed: insufficient evidence was available to determine whether this position is a mutational hotspot or critical functional domain.
Details ▾Hide ▴
Reasoning
PM1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PM3Not assessed: insufficient evidence was available to evaluate this criterion.
Details ▾Hide ▴
Reasoning
PM3 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PM5Not assessed: insufficient evidence was available to determine whether a different pathogenic missense change is known at this residue.
Details ▾Hide ▴
Reasoning
PM5 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PM6Not assessed: insufficient evidence was available to determine whether the variant arose de novo.
Details ▾Hide ▴
Reasoning
PM6 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PP1Not assessed: insufficient evidence was available to evaluate co-segregation with disease in affected relatives.
Details ▾Hide ▴
Reasoning
PP1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
PP2Not assessed: insufficient evidence was available to evaluate this criterion.
Details ▾Hide ▴
Reasoning
PP2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
BS3Not assessed: insufficient evidence was available from functional studies to determine whether the variant lacks a damaging effect.
Details ▾Hide ▴
Reasoning
BS3 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
BS4Not assessed: insufficient evidence was available to evaluate segregation among affected family members.
Details ▾Hide ▴
Reasoning
BS4 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
BP1Not assessed: insufficient evidence was available to evaluate this criterion.
Details ▾Hide ▴
Reasoning
BP1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
BP2Not assessed: insufficient evidence was available to evaluate this criterion.
Details ▾Hide ▴
Reasoning
BP2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: Hermes timed out after 200s and left no usable output_file
attempt 2: Hermes timed out after 200s and left no usable output_file
attempt 3: Hermes timed out after 200s and left no usable output_file
Not applicable · 8· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: PVS1 is limited to null variants, and this is a missense substitution (p.Val1125Ala) with no predicted splice impact (SpliceAI max delta 0.00).
Details ▾Hide ▴
Reasoning
NM_001127510.3:c.3374T>C is a single-nucleotide substitution predicted to produce NP_001120982.1:p.(Val1125Ala), a missense amino-acid substitution (VEP most_severe_consequence 'missense_variant'; consequence_class 'missense'). PVS1 under the governing ClinGen InSiGHT APC VCEP v2.1 framework is scoped to null variants ('Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1)'), and the APC decision-tree lists (A-E) enumerate specific nonsense/frameshift/canonical splice-site alleles; c.3374T>C is not a null allele and does not appear in any PVS1 list. SpliceAI predicts no splice impact (all four delta scores 0.00; max delta 0.00), so there is no basis to consider this presumed-missense allele as a splice-disrupting/null allele under the decision tree. The variant is therefore outside the scope of PVS1; LOF is an established mechanism for APC (per the VCEP), but this allele type cannot trigger PVS1.
Evidence considered
case_summary.json normalization: NM_001127510.3:c.3374T>C corresponds to NP_001120982.1:p.(Val1125Ala); gnomAD-Canada VEP most_severe_consequence is 'missense_variant' (5-112838968-T-C), and evidence.json consequence_class is 'missense'.
cspec (InSiGHT APC VCEP v2.1) PVS1 rule text: 'Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1].' The APC VCEP therefore routes PVS1 through the gene-specific decision tree rather than generic PVS1 defaults.
vcep_materials summary of Fig.-1_APC_PVS1_decision-tree_2023-10-20.pdf: Lists A (PVS1), B (PVS1_Strong), C (PVS1_Moderate), D (PVS1_Supporting) and E (N/A) enumerate specific truncating/splice-site variants (e.g., c.136-1G>A,C,T; c.646-1G>A,C,T; c.220G>A,C,T; c.645+1G>A,C,T; ... up to approx. c.1959 positions); none corresponds to c.3374T>C and none applies to an exonic missense SNV.
spliceai evidence.json record: SpliceAI max delta score = 0.00 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0), evidence_sentence 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00)' - the variant is a pure missense allele with no predicted splice effect, excluding a PVS1 splice-disruption pathway.
The APC VCEP supplementary material confirms 'APC is a gene where LOF is the predominant mechanism', so the gene-level gate is met, but PVS1 is not applicable because the variant itself is not a null (nonsense/frameshift/canonical splice) allele.
PM4VCEPNot applicable: APC VCEP v2.1 does not use PM4, and the criterion requires a protein-length change that a single missense substitution does not produce.
Details ▾Hide ▴
Reasoning
The ClinGen InSiGHT APC VCEP v2.1 specification declares PM4 'Not Applicable' for APC (cspec applicability field), and the VCEP supplementary material states PM4 is 'Not used due to limited available data.' Independently, PM4 requires a protein length change from an in-frame deletion/insertion or stop-loss variant; c.3374T>C is a single-nucleotide missense substitution (p.Val1125Ala) that changes one amino acid without altering protein length and creates no insertion, deletion, or stop-loss. PM4 is therefore not applicable under either the VCEP framework or the underlying criterion mechanics.
Evidence considered
case_summary.json cspec.criteria list: {"label": "PM4", "applicability": "Not Applicable"} explicitly declared by the InSiGHT APC VCEP specification v2.1.
vcep_materials summary of APC_specifications_supplementary-material_V2.pdf (Page 4 table): PM4 row comment 'Not used due to limited available data.' - the VCEP does not apply PM4 to APC variants.
case_summary.json normalization: c.3374T>C is a T>C single-nucleotide change producing p.(Val1125Ala); a single amino-acid substitution with no change in protein length, i.e., not an in-frame indel, duplication, or stop-loss event that PM4 addresses.
PP4VCEPNot applicable: the APC VCEP excludes PP4 because phenotype and family-history specificity is already captured under PS4.
Details ▾Hide ▴
Reasoning
The ClinGen InSiGHT APC VCEP v2.1 (cspec) declares PP4 Not Applicable: patient phenotype/family-history specificity is already captured by the PS4 phenotype-point specification (supplementary material: 'Already captured by the specifications of PS4'). Under the governing VCEP framework PP4 must not be applied, so it is not scored here regardless of phenotype data.
Evidence considered
cspec (ClinGen InSiGHT APC VCEP v2.1) lists PP4 applicability as Not Applicable.
vcep_apc_specifications_supplementary_material_v2 (APC VCEP specification table, page 5) states for PP4: 'Already captured by the specifications of PS4' - phenotype specificity is scored through the PS4 point system rather than as a separate criterion.
PP5VCEPNot applicable: the APC VCEP does not use PP5, and no ClinVar expert-panel pathogenic submission exists for c.3374T>C.
Details ▾Hide ▴
Reasoning
Two independent reasons PP5 cannot apply. (1) The ClinGen InSiGHT APC VCEP v2.1 (cspec) declares PP5 Not Applicable ('Not used as recommended by Biesecker et al. 2018'). (2) PP5 is applied in this pipeline only for an exact-variant ClinVar expert-panel classification of Pathogenic/Likely Pathogenic; the ClinVar record for c.3374T>C (VariationID 132749) has 0 expert-panel submissions (expert_panel_submissions: 0), and the aggregate Likely benign/Benign labels come from 13-14 ordinary single-submitter clinical laboratory assertions with review status 'criteria provided, single submitter'. No expert-panel pathogenic assertion exists, and the ClinVar-linked guideline papers (PMID:15604628, PMID:22138009, PMID:25356965, PMID:25373533) tagged as PP5 candidates contain no mention of this variant in full text. PP5 must not be triggered.
Evidence considered
cspec (ClinGen InSiGHT APC VCEP v2.1) lists PP5 applicability as Not Applicable.
vcep_apc_specifications_supplementary_material_v2 (APC VCEP specification table, page 5) states PP5 is 'Not used as recommended by Biesecker et al. 2018'.
clinvar (VariationID 132749): submission audit reports expert_panel_submissions = 0; 16 total submissions are ordinary laboratory assertions (9 Likely benign, 4 Benign, 1 Uncertain significance, 1 benign), review status 'criteria provided, single submitter' - not an expert-panel classification, so PP5 is not engaged under the exact-variant expert-panel rule.
PMID:15604628, PMID:22138009, PMID:25356965, PMID:25373533 (ClinVar-cited papers tagged with PP5 candidate theme) were checked via paper_extracts: none mentions APC c.3374T>C or p.V1125A anywhere in full text (variant_mentioned: false), so none provides a reputable-source variant classification.
BP3VCEPNot applicable: APC VCEP v2.1 excludes BP3, and the variant is a missense substitution rather than an in-frame indel in a repeat region.
Details ▾Hide ▴
Reasoning
The ClinGen InSiGHT APC VCEP v2.1 specification explicitly marks BP3 as 'Not Applicable' for APC, so the governing VCEP framework (not generic ACMG fallback) controls and BP3 is not used for this gene. Independently, BP3 concerns in-frame indels/duplications in a repeat region without known function, whereas c.3374T>C is a missense SNV (p.Val1125Ala) with no in-frame deletion/insertion and no length change; the criterion is mechanistically inapplicable to this allele regardless of the explicit VCEP flag.
Evidence considered
case_summary.json cspec.criteria list: {"label": "BP3", "applicability": "Not Applicable"} explicitly declared by the InSiGHT APC VCEP specification v2.1; VCEP declaration takes precedence over generic ACMG BP3.
The variant is a missense single-nucleotide substitution (NP_001120982.1:p.(Val1125Ala)), not an in-frame insertion/deletion or duplication in a repeat region, so BP3's premise (repeat-region length-neutral indel with no known functional impact) cannot apply.
BP4N/ANot applicable: the APC VCEP restricts BP4 to synonymous or intronic variants; c.3374T>C is a missense change.
Details ▾Hide ▴
Reasoning
The APC InSiGHT VCEP (cspec v2.1) BP4 rule states verbatim: 'Missense variants: BP4 is not applicable.' This variant is a missense change (c.3374T>C, p.(Val1125Ala)) rather than a synonymous or intronic variant, so BP4 cannot be applied regardless of any splice-prediction result. The SpliceAI no-impact finding (max delta 0.00) was therefore NOT counted as BP4 evidence, avoiding double-counting the same prediction across PP3/BP4/BP7. The generic missense in-silico path is likewise closed because the VCEP BP4 rule reserves BP4 for synonymous/intronic variants and states BP4 is not applicable to missense variants.
Rule
APC VCEP (cspec v2.1) BP4_Supporting: 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 InSiGHT VCEP (cspec v2.1) BP4 supporting 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.'
Variant class confirmed as missense (p.Val1125Ala; VEP most_severe_consequence 'missense_variant' in gnomAD-Canada record; ClinVar variant title p.Val1125Ala), placing it in the missense category for which the APC VCEP declares BP4 not applicable.
BP6VCEPNot applicable: the APC VCEP does not use BP6, and no ClinVar expert-panel benign submission exists for c.3374T>C.
Details ▾Hide ▴
Reasoning
Two independent reasons BP6 cannot apply. (1) The ClinGen InSiGHT APC VCEP v2.1 (cspec) declares BP6 Not Applicable ('not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee'). (2) BP6 is applied in this pipeline only for an exact-variant ClinVar expert-panel classification of Benign/Likely Benign; the ClinVar record for c.3374T>C (VariationID 132749) has 0 expert-panel submissions, and the aggregate Likely benign/Benign labels are ordinary single-submitter clinical laboratory assertions ('criteria provided, single submitter'). Ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6, so BP6 is not met by any applicable evidence.
Evidence considered
cspec (ClinGen InSiGHT APC VCEP v2.1) lists BP6 applicability as Not Applicable.
vcep_apc_specifications_supplementary_material_v2 (BP6 instructions): 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
clinvar (VariationID 132749): submission audit reports expert_panel_submissions = 0; the Benign/Likely benign labels are from 13-14 clinical laboratories with 'criteria provided, single submitter' review status - ordinary laboratory submissions, not an expert-panel classification, so BP6 is not engaged under the exact-variant expert-panel rule.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants with no predicted splice impact; c.3374T>C is an exonic missense.
Details ▾Hide ▴
Reasoning
The APC InSiGHT VCEP (cspec v2.1) BP7 supporting rule applies only to '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.' The variant under assessment is an exonic missense SNV (c.3374T>C, p.(Val1125Ala)) - it is neither synonymous nor intronic - so BP7 is outside the scope of the criterion as specified by the VCEP and is not applied. The SpliceAI no-impact result is consequently not used as BP7 evidence.
Rule
APC VCEP (cspec v2.1) BP7_Supporting: A synonymous (silent) or intronic variant at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
APC InSiGHT VCEP (cspec v2.1) BP7 supporting 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.'
Variant class confirmed as missense (c.3374T>C, p.(Val1125Ala)), which does not satisfy the synonymous/intronic precondition of the APC VCEP BP7 rule.
AF 0.00013 · 211 / 1,613,984 alleles · 0 hom · FAF 0.0033
East Asian170 / 44,878
0.0038
Remaining individuals37 / 62,484
0.00059
Admixed American2 / 59,998
3.3e-05
African/African American1 / 74,908
1.3e-05
European (non-Finnish)1 / 1,180,020
8.5e-07
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0006 · 169 / 282,016 alleles · 1 hom · FAF 0.007
East Asian164 / 19,922
0.00821 hom
Remaining individuals4 / 7,198
0.00056
African/African American1 / 24,876
4e-05
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000130732; MAF= 0.01307%, 211/1613984 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00378805; MAF= 0.37880%, 170/44878 alleles, homozygotes = 0); grpmax FAF= 0.00332268.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000599257; MAF= 0.05993%, 169/282016 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00823211; MAF= 0.82321%, 164/19922 alleles, homozygotes = 1); grpmax FAF= 0.00700099.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009231103388357949, 17/18416 alleles, homozygotes = 0).
PP3Not met: the APC VCEP permits only splicing predictions for missense variants, and SpliceAI reports max delta 0.00 - no predicted splicing impact.
Details ▾Hide ▴
Reasoning
Variant is a missense SNV (NM_001127510.3:c.3374T>C, p.(Val1125Ala), confirmed missense_variant by VEP/ClinVar/Mutalyzer). The governing APC InSiGHT VCEP (cspec v2.1) PP3 supporting rule states that for missense variants, computational prediction models for conservation/evolution etc. must NOT be used, and only in silico splicing predictors may be used to reveal possible splicing effects (non-canonical splice variants require multiple predictors supporting a deleterious effect). Under this specification the missense in-silico path (REVEL 0.455; BayesDel 0.3287, both retrieved by prefetch) is not usable for PP3, and BayesDel additionally has no verified published calibration threshold available to this pipeline. On the permitted splice-impact path, SpliceAI (the first of the VCEP's recommended splice predictors) reports max delta = 0.00 with DS_AG = DS_AL = DS_DG = DS_DL = 0.0, i.e., no predicted disruption of a native splice site and no predicted creation of a cryptic splice site. There is therefore no computational evidence of a deleterious splicing effect, so PP3 is not met.
Rule
APC VCEP (cspec v2.1) PP3_Supporting: Missense variants - do not use computational prediction models; in silico splicing predictors should be used to reveal possible splicing effects. Non-canonical splicing variants - multiple in silico splicing predictors support a deleterious effect.
Evidence considered
APC InSiGHT VCEP (cspec v2.1) PP3 supporting 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.
SpliceAI Lookup (source key 'spliceai') queried with NM_001127510.3:c.3374T>C (GRCh37 5-112174665-T-C): max delta score = 0.00; DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0 - no significant splice impact predicted (no native site loss, no cryptic site gain).
Prefetch retrieved missense predictor scores (REVEL 0.455, BayesDel 0.328746) but these were not applied to PP3: the APC VCEP explicitly excludes generic computational prediction models for missense variants, and BayesDel has no verified published threshold available to this pipeline.
APC VCEP PP3 does not pre-assign PP3 for this variant position in any gene-specific lookup material; no such lookup spreadsheet exists in the case's VCEP files (index.txt absent, user_files empty).
Still missing
Only SpliceAI was run for this case; MaxEntScan and VarSeak (the other splice programs the APC VCEP recommends, see PS1 instructionsToUse) were not retrieved. A positive splice-impact call from a second algorithm cannot be formally excluded, although a SpliceAI max delta of 0.00 provides no support for PP3.
BP4N/ANot applicable: the APC VCEP restricts BP4 to synonymous or intronic variants; c.3374T>C is a missense change.
Details ▾Hide ▴
Reasoning
The APC InSiGHT VCEP (cspec v2.1) BP4 rule states verbatim: 'Missense variants: BP4 is not applicable.' This variant is a missense change (c.3374T>C, p.(Val1125Ala)) rather than a synonymous or intronic variant, so BP4 cannot be applied regardless of any splice-prediction result. The SpliceAI no-impact finding (max delta 0.00) was therefore NOT counted as BP4 evidence, avoiding double-counting the same prediction across PP3/BP4/BP7. The generic missense in-silico path is likewise closed because the VCEP BP4 rule reserves BP4 for synonymous/intronic variants and states BP4 is not applicable to missense variants.
Rule
APC VCEP (cspec v2.1) BP4_Supporting: 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 InSiGHT VCEP (cspec v2.1) BP4 supporting 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.'
Variant class confirmed as missense (p.Val1125Ala; VEP most_severe_consequence 'missense_variant' in gnomAD-Canada record; ClinVar variant title p.Val1125Ala), placing it in the missense category for which the APC VCEP declares BP4 not applicable.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants with no predicted splice impact; c.3374T>C is an exonic missense.
Details ▾Hide ▴
Reasoning
The APC InSiGHT VCEP (cspec v2.1) BP7 supporting rule applies only to '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.' The variant under assessment is an exonic missense SNV (c.3374T>C, p.(Val1125Ala)) - it is neither synonymous nor intronic - so BP7 is outside the scope of the criterion as specified by the VCEP and is not applied. The SpliceAI no-impact result is consequently not used as BP7 evidence.
Rule
APC VCEP (cspec v2.1) BP7_Supporting: A synonymous (silent) or intronic variant at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
APC InSiGHT VCEP (cspec v2.1) BP7 supporting 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.'
Variant class confirmed as missense (c.3374T>C, p.(Val1125Ala)), which does not satisfy the synonymous/intronic precondition of the APC VCEP BP7 rule.
Single nucleotide polymorphisms of the APC gene and colorectal cancer risk: a case-control study in Taiwan.
Chen SP et al. · 2006
In this Taiwanese case-control study (80 CRC patients, 74 healthy adults; entire APC coding region screened by PCR/DHPLC/bidirectional sequencing of germline DNA), the missense variant p.V1125A (g.3374T>C) was identified in three subjects in the CRC patient group and one subject in the healthy control group, and is reported as a variant not previously described. Its prevalence did not differ significantly between the patient and health examination groups; no genotype-phenotype or segregation analysis is presented. The authors speculate p.V1125A and p.S1126R (close to the first 15-amino-acid beta-catenin binding repeat) might disrupt putative APC cell-signaling function, but state this needs experimental demonstration; no functional assay was performed.
Of the 3 observed missense substitutions, p.V1125A and p.S1126R represent variants not previously reported. p.V1125A was identified in three subjects in the patient group and in one subject in the health examination group, but p.S1126R was found only in the health examination group. However, the prevalence of these variants did not differ significantly between the patient and health examination groups.
Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas.
Azzopardi D et al. · 2008
The paper explicitly lists V1125A among 61 different rare (MAF <2%) inherited nonsynonymous APC variants found by sequencing the full APC ORF in 691 unrelated North American patients with colorectal adenomas (CRAs). V1125A appears only in Table 1, in the non-FAP non-MAP patient group with 11-99 CRAs, with no parenthetical count, indicating it was identified in a single patient. No variant-specific functional data are reported: the beta-catenin-regulated transcription assays tested only 16 variants in the 20-amino-acid beta-catenin down-regulating domain (codons 1262-2033), and V1125A falls in the 15-amino-acid repeat beta-catenin binding domain (codons 1020-1169), so it was not among the 7 of 16 variants shown to impair CRT. In silico predictions were reported only in aggregate for all 61 variants.
Table 1, row '11 to 99 CRAs' (non-FAP non-MAP patients, APC ORF); note under Table 1 states each variant was identified in a single patient/control within each group unless otherwise indicated in parentheses
Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?
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= 0.000130732; MAF= 0.01307%, 211/1613984 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00378805; MAF= 0.37880%, 170/44878 alleles, homozygotes = 0); grpmax FAF= 0.00332268.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000599257; MAF= 0.05993%, 169/282016 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00823211; MAF= 0.82321%, 164/19922 alleles, homozygotes = 1); grpmax FAF= 0.00700099.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0009231103388357949, 17/18416 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 132749)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.455. BayesDel score = 0.328746.
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; COSV57340743, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.2.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.