Classification rationale

PM2 BP4BP7 Likely Benign

APC c.4413A>G synonymous · exon 17

PM2 supporting: the variant is absent from gnomAD v2.1.1 non-cancer exomes, with AF 0 and allele count 0. BP4 supporting: SpliceAI maximum delta 0.001 and Pangolin predictions indicate no significant splice impact. BP7 supporting: the synonymous variant has concordant near-zero splice predictions from multiple algorithms.

PM2 + BP4 + BP7 → Likely Benign

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.

Gene diagram · NM_001127510.3 · variants mapped to exon structure

APC NM_001127510.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting: gnomAD v2.1.1 non-cancer exomes show AF 0 with allele count 0, below the APC PM2 threshold of 0.00001.

The APC InSiGHT VCEP specifies the total population from gnomAD v2.1.1 non-cancer and defines PM2_Supporting as AF <= 0.000003 for allele count > 1 or AF < 0.00001 for allele count <= 1.The variant is absent from the gnomAD v2.1 non-cancer exome dataset, equivalent to allele count 0 and AF 0; this satisfies the allele-count-at-most-1 branch of the VCEP PM2 rule.

cspec ↗gnomad_v2 ↗

BP4 supporting Benign

Met at supporting: SpliceAI max delta 0.001 is below the <=0.1 BP4 threshold and predicts no significant splice impact.

The APC VCEP states that BP4 Supporting applies to synonymous or intronic variants when multiple in silico splicing predictors suggest no impact on the gene or gene product.SpliceAI maximum delta is 0.001, below the generic BP4 supporting cutoff of 0.1 from Jaganathan et al. 2019 (PMID:30661751).The available Pangolin outputs are 0.012 and -0.003, concordant with the near-zero SpliceAI result and no predicted splice impact.

cspec ↗spliceai ↗

BP7 supporting Benign

Met at supporting: the synonymous variant has concordant near-zero splice predictions, including SpliceAI max delta 0.001.

The APC VCEP BP7 rule covers synonymous variants when multiple splice-prediction algorithms predict no impact to the splice consensus sequence or creation of a new splice site.SpliceAI maximum delta is 0.001, with individual delta scores from 0.000 to 0.001; Pangolin outputs are 0.012 and -0.003, concordant with no predicted splice impact.BP7 is assessed independently as the synonymous-variant benign criterion and does not double-count the same prediction as PP3 or BP4.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS2 Not assessed: no proband phenotype, parental genotypes, confirmed maternity or paternity, or de novo observation is documented for c.4413A>G.

PS3 Not assessed: no variant-specific RNA or protein assay result was identified to meet the APC VCEP PS3 requirements.

PS4 Not assessed: no exact-variant phenotype points, case-control enrichment estimate, odds ratio, relative risk, or confidence interval is available for the APC PS4 rules.

PM6 Not assessed: no assumed de novo observation, proband phenotype, parental testing, or de novo score is documented for c.4413A>G.

PP1 Not assessed: zero affected relatives, phenotype-positive carriers, pedigrees, or informative meioses are documented for c.4413A>G.

PP3 Not met: SpliceAI max delta 0.001 is below the 0.2 PP3 supporting threshold for a deleterious splice effect.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1.1 non-cancer exomes, below the APC BA1 threshold of 0.001.

BS1 Not met: the variant is absent from gnomAD v2.1.1 non-cancer exomes, below the APC BS1 threshold of 0.00001.

BS2 Not met: gnomAD v2.1.1 non-cancer exomes show zero homozygous observations, below the APC BS2 requirement of at least 2.

BS3 Not assessed: no variant-specific RNA or protein assay demonstrated normal APC function or splicing under the VCEP BS3 requirements.

BS4 Not assessed: no affected non-carrier or qualifying phenotype score is documented to meet the APC BS4 threshold of 0.5 or 1 point.

BP2 Not assessed: no affected-proband phase data, in-trans pathogenic APC variant, or three qualifying unknown-phase co-occurrences are documented.

BP5 Not assessed: no qualifying alternate-gene Pathogenic or Likely pathogenic variant and no documented colorectal polyposis phenotype are available for the APC BP5 rule.

N/A · 12 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23902e-05; MAF= 0.00124%, 20/1614184 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.79939e-05; MAF= 0.00480%, 3/62508 alleles, homozygotes = 0); grpmax FAF= 7.63e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0012% · 20 / 1,614,184
0 hom · FAF 0.00076%

Remaining individuals 3 / 62,508	0.0048%
European (Finnish) 1 / 64,042	0.0016%
African/African American 1 / 75,040	0.0013%
European (non-Finnish) 15 / 1,180,032	0.0013%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 377493)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57335057, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

11598466 ↗ Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. CLINVAR

20301519 ↗ APC-Associated Polyposis Conditions. CLINVAR

24310308 ↗ ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). CLINVAR

25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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