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APCc.-11G>CUncertain significance
Print report
Variant interpretation report

APC c.-11G>C, p.(=)

NM_001127510.3:c.-11G>C NP_001120982.1:p.(=) Synonymous · exon 3 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at supporting strength: the variant is absent from gnomAD v2.1.1 non-cancer, giving AF 0 versus the APC PM2 threshold of <0.001% (0.00001) when AC <=1.

Benign criteria applied · 1
BP7Supporting
BP7 · supporting

Met, Supporting: synonymous variant with SpliceAI maximum delta 0.013 and Pangolin scores 0.012/-0.002 supports no splice impact.

Recorded classification: Uncertain significance

VUS: PM2 (supporting) and BP7 (supporting) are met, but the APC InSiGHT VCEP's criteria-combination rules do not yield a definitive classification.

02The sources

Evidence at a glance

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

SpliceAI score
0.013 maximum delta

Recorded SpliceAI maximum delta score: 0.013. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP7 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

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 ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
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: 2 met · 3 not met · 9 not assessed · 14 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 four requested segregation/de novo criteria remain not assessed because the available case evidence contains no pedigree, parental testing, affected-relative testing, or phenotype-point data needed by the APC VCEP rules.

The APC Version 2.1 VCEP framework governs this case.

The synonymous consequence makes BP7 the applicable computational benign criterion; PP3 and BP4 are not applicable under the stated missense or intronic/splice-region scope.

BP7 is met at Supporting strength because SpliceAI and Pangolin both predict no meaningful splice impact.

Met · 2

PM2 SupportingMet at supporting strength: the variant is absent from gnomAD v2.1.1 non-cancer, giving AF 0 versus the APC PM2 threshold of <0.001% (0.00001) when AC <=1. Details ▾Hide ▴
Reasoning

The APC VCEP specifies PM2 Supporting using the total population from the gnomAD v2.1.1 non-cancer dataset: allele frequency <= 0.0003% (0.000003) when allele count is greater than 1, or allele frequency < 0.001% (0.00001) when allele count is at most 1. NM_001127510.3:c.-11G>C is absent from gnomAD v2.1.1 non-cancer, indicating no observed alternate alleles and an allele frequency of 0, which satisfies the allele-count-at-most-1 branch.

Rule
Rare in controls: AF <= 0.0003% (0.000003) if AC > 1 OR AF < 0.001% (0.00001) if AC <= 1; use the total population from the gnomAD v2.1.1 non-cancer dataset.
Evidence considered
  • The APC InSiGHT VCEP specifies PM2 Supporting for AF <= 0.0003% (0.000003) if AC > 1 or AF < 0.001% (0.00001) if AC <= 1, using the gnomAD v2.1.1 non-cancer dataset.
  • The variant is reported absent from gnomAD v2.1.1 non-cancer; absence corresponds to no observed alternate allele and AF 0 in the queried dataset, satisfying the AC <= 1 branch.
Sources
cspec ↗gnomad_v2 ↗
BP7 SupportingMet, Supporting: synonymous variant with SpliceAI maximum delta 0.013 and Pangolin scores 0.012/-0.002 supports no splice impact. Details ▾Hide ▴
Reasoning

BP7 applies because NM_001127510.3:c.-11G>C is annotated as a synonymous variant (NP_001120982.1:p.(=)). The APC VCEP assigns BP7 at Supporting strength when multiple splicing prediction algorithms predict no impact to the splice consensus sequence or creation of a new splice site. SpliceAI reports a maximum delta score of 0.013, with DS_AG 0.009, DS_DG 0.013, DS_AL 0.000, and DS_DL 0.000; Pangolin scores are 0.012 and -0.002. These independent predictor results support no meaningful splice impact, so BP7 is met at Supporting strength.

Rule
APC VCEP 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 or creation of a new splice site.
Evidence considered
  • The variant is annotated as synonymous with protein consequence NP_001120982.1:p.(=).
  • The APC Version 2.1 VCEP BP7 rule requires a synonymous or qualifying intronic variant with multiple splicing predictors indicating no splice impact.
  • SpliceAI reports max delta 0.013: DS_AG 0.009, DS_AL 0.000, DS_DG 0.013, and DS_DL 0.000.
  • Pangolin reports splice scores of 0.012 and -0.002, consistent with no significant predicted splice effect.
Sources
cspec ↗spliceai ↗

Not met · 3 · evaluated, threshold not reached

BA1 Not met: the variant is absent from gnomAD v2.1.1 non-cancer, below the APC VCEP BA1 threshold of 0.1% (0.001). Details ▾Hide ▴
Reasoning

The APC VCEP specifies BA1 when the gnomAD Popmax filtering allele frequency is at least 0.1% (0.001), using the gnomAD v2.1.1 non-cancer dataset. NM_001127510.3:c.-11G>C is absent from gnomAD v2.1 and its non-cancer subset, and is also absent from gnomAD v4.1; therefore there is no population frequency meeting the BA1 threshold.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001); use the non-cancer dataset from gnomAD v2.1.1.
Evidence considered
  • The APC InSiGHT VCEP specifies BA1 at gnomAD Popmax filtering AF >= 0.1% (0.001) and recommends the gnomAD v2.1.1 non-cancer dataset.
  • The variant is reported absent from gnomAD v2.1, including the non-cancer subset, and absent from gnomAD v4.1; no allele frequency or Popmax AF is reported.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant is absent from gnomAD v2.1.1 non-cancer, below the APC VCEP BS1 threshold of 0.001% (0.00001). Details ▾Hide ▴
Reasoning

The APC VCEP specifies BS1 when the gnomAD Popmax filtering allele frequency is at least 0.001% (0.00001), using the gnomAD v2.1.1 non-cancer dataset. NM_001127510.3:c.-11G>C is absent from gnomAD v2.1 and its non-cancer subset, and is also absent from gnomAD v4.1; therefore the observed population data do not meet BS1.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001); use the non-cancer dataset from gnomAD v2.1.1.
Evidence considered
  • The APC InSiGHT VCEP specifies BS1 at gnomAD Popmax filtering AF >= 0.001% (0.00001) and recommends the gnomAD v2.1.1 non-cancer dataset.
  • The variant is reported absent from gnomAD v2.1, including the non-cancer subset, and absent from gnomAD v4.1; no allele frequency or Popmax AF is reported.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 Not met: gnomAD v2.1.1 non-cancer reports no homozygous observations, versus the APC VCEP threshold of at least 2 homozygotes. Details ▾Hide ▴
Reasoning

The APC VCEP allows BS2 Strong for at least two homozygous observations or for at least 10 healthy-individual points, and specifically permits the gnomAD v2.1.1 non-cancer dataset to search for homozygous individuals. The variant is absent from that non-cancer dataset, with no homozygous observations reported, and the case contains no qualifying healthy-individual observations; BS2 is therefore not met.

Rule
>= 10 points for healthy individuals OR >= 2 times in homozygous state; gnomAD v2.1.1 non-cancer may be used to search for homozygous individuals.
Evidence considered
  • The APC InSiGHT VCEP defines BS2 Strong as at least 10 healthy-individual points or at least 2 observations in the homozygous state.
  • The VCEP states that gnomAD v2.1.1 non-cancer may be used to search for homozygous individuals, while it cannot establish qualifying heterozygous healthy individuals.
  • The variant is absent from gnomAD v2.1.1 non-cancer, so no homozygous observations are available; no qualifying healthy-individual clinical observations are present in the case evidence.
Sources
cspec ↗gnomad_v2 ↗

Not assessed · 9 · no assessment recorded

PS2 Not assessed: no proband phenotype score, parental testing, or documented de novo observation is available to calculate the APC VCEP PS2 score. Details ▾Hide ▴
Reasoning

The APC VCEP requires PS2 de novo scoring from phenotype points and parental-relationship confirmation: confirmed maternity and paternity contribute 2 points for a proband with at least 1 phenotype point, or 1 point when parental relationships are unconfirmed; the available case evidence contains no proband phenotype scoring, parental testing, or de novo observation for APC c.-11G>C, so PS2 cannot be assigned.

Rule
APC VCEP Version 2.1: PS2 very strong for >=4 de novo scores, strong for 2-3.5 scores, and moderate for 1-1.5 scores; de novo scores are curated using Tables 1 and 2.
Evidence considered
  • The APC VCEP Version 2.1 specifies PS2 as very strong for at least 4 de novo scores, strong for 2-3.5, and moderate for 1-1.5; its Table 1/2 scoring depends on phenotype points and confirmed versus unconfirmed parental relationships.
  • No case-specific proband phenotype, parental test result, maternity/paternity confirmation, or de novo observation is documented in the available evidence.
Still missing
  • Document the proband's APC-consistent phenotype and phenotype-point score.
  • Provide parental genotyping showing whether the variant is absent in both parents and whether maternity and paternity are confirmed.
  • Document whether the proband has no relevant family history.
Sources
cspec ↗
PS3 Not assessed: no variant-specific RNA or protein assay result is available to satisfy the APC VCEP PS3 requirements. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification requires variant-specific functional evidence for PS3. For this synonymous upstream variant, the governing PS3 rules require an RNA assay demonstrating a premature stop codon or specified exon skipping/loss, with transcript-level calibration (including absence of full-length transcript, <10%, or other specified abnormal transcript patterns), or an applicable protein assay showing increased β-catenin-regulated transcription or decreased β-catenin binding. The available evidence contains no assay of NM_001127510.3:c.-11G>C and no variant-specific transcript or protein result; therefore PS3 cannot be assessed at any strength.

Rule
APC InSiGHT VCEP Version 2.1 PS3: RNA assays must show specified abnormal transcript consequences with the applicable transcript-abundance calibration; specified protein assays may show increased β-catenin-regulated transcription or decreased β-catenin binding for variants within the β-catenin binding domain.
Evidence considered
  • The APC InSiGHT VCEP Version 2.1 PS3 specification requires defined abnormal RNA findings, including premature stop codon or specified exon skipping/loss, with strength calibrated by full-length transcript abundance; it also permits specified protein assay findings for variants in the β-catenin binding domain.
  • The case evidence identifies NM_001127510.3:c.-11G>C as synonymous/upstream with predicted protein consequence NP_001120982.1:p.(=), but reports no variant-specific RNA, mRNA, splicing, or protein functional assay result.
  • The ACMG/AMP guideline paper states that mRNA assays can evaluate untranslated-region variants, but it reports no APC-specific assay or observation for this variant.
Still missing
  • Variant-specific constitutional RNA assay with quantitative full-length transcript and exon/intronic transcript characterization is unavailable.
  • No variant-specific protein assay result is available; the APC protein-assay PS3 option is limited to the β-catenin binding domain.
Sources
cspec ↗PMID:25741868 ↗
PS4 Not assessed: no proband phenotype, phenotype-point total, or case-control enrichment estimate is available for this exact APC variant. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PS4 using phenotype points: supporting requires 1-1.5 points, moderate 2-3.5, strong 4-15.5, and very strong at least 16, with phenotype curation defined in Table 1. The available case evidence contains no proband phenotype, colorectal polyp count, family-history details, or case-control enrichment estimate for NM_001127510.3:c.-11G>C, so no phenotype points can be assigned and PS4 cannot be assessed.

Rule
PS4: >=16 phenotype points = Very Strong; 4-15.5 = Strong; 2-3.5 = Moderate; 1-1.5 = Supporting; phenotype points are curated using APC VCEP Table 1.
Evidence considered
  • The APC VCEP rule states that PS4 strength is based on phenotype points: 1-1.5 supporting, 2-3.5 moderate, 4-15.5 strong, and >=16 very strong.
  • The exact-variant literature extraction for PMID:25394175 reports no mention of c.-11G>C and no variant-specific cohort analysis; it only provides general FAP referral findings.
Still missing
  • Proband phenotype details and phenotype-point curation under APC Table 1 are unavailable.
  • No case-control relative risk, odds ratio, confidence interval, or qualifying unrelated-case series is available.
Sources
cspec ↗PMID:25394175 ↗
PM6 Not assessed: no assumed de novo observation or phenotype-based de novo score is documented for APC c.-11G>C. Details ▾Hide ▴
Reasoning

The APC VCEP requires PM6 de novo scoring when parental relationships are not confirmed: 2-3.5 de novo scores support strong PM6, 1-1.5 support moderate PM6, and 0.5 supports supporting PM6; no assumed de novo observation, phenotype score, or parental-relationship information is available for APC c.-11G>C, so PM6 cannot be assigned.

Rule
APC VCEP Version 2.1: PM6 strong for 2-3.5 de novo scores, moderate for 1-1.5 scores, and supporting for 0.5 scores; de novo scores are curated using Tables 1 and 2.
Evidence considered
  • The APC VCEP Version 2.1 specifies PM6 as strong for 2-3.5 de novo scores, moderate for 1-1.5 scores, and supporting for 0.5 de novo scores, with de novo scores curated using Tables 1 and 2.
  • No case-specific assumed de novo finding, phenotype score, parental testing, or parental-relationship status is documented in the available evidence.
Still missing
  • Document the proband's APC-consistent phenotype and phenotype-point score.
  • Provide evidence that the variant was absent from tested parents or otherwise document the basis for an assumed de novo event.
  • State whether maternity and paternity were confirmed, because this determines whether PS2 or PM6 applies.
Sources
cspec ↗
PP1 Not assessed: no affected-relative genotypes, family structure, or meiosis count is documented to evaluate APC segregation. Details ▾Hide ▴
Reasoning

The APC VCEP assigns PP1 supporting for segregation in 3-4 meioses, moderate for 5-6 meioses in at least one family, and strong for at least 7 meioses in at least 2 families; no affected relatives, transmitting parents, family structure, or meiosis count is documented for APC c.-11G>C, so PP1 cannot be assigned.

Rule
APC VCEP Version 2.1: PP1 supporting for 3-4 meioses in at least 1 family, moderate for 5-6 meioses in at least 1 family, and strong for >=7 meioses in at least 2 families.
Evidence considered
  • The APC VCEP Version 2.1 specifies PP1 supporting for 3-4 segregating meioses in at least 1 family, moderate for 5-6 meioses in at least 1 family, and strong for at least 7 meioses in at least 2 families.
  • No case-specific pedigree, affected-relative testing, transmission data, or informative meiosis count is documented in the available evidence.
Still missing
  • Provide a pedigree identifying affected and unaffected relatives and their clinical phenotypes.
  • Provide variant test results for informative relatives and the phase/transmission relationships.
  • Count independent informative meioses and identify the number of families represented.
Sources
cspec ↗
BS3 Not assessed: no variant-specific RNA assay with required controls or qualifying protein assay demonstrates preserved APC function. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification requires a well-established variant-specific benign functional result. For this synonymous upstream variant, BS3 Strong requires a constitutional RNA assay showing no mRNA aberration together with demonstrated biallelic expression and/or nonsense-mediated decay inhibition; BS3 Supporting permits the same RNA result without those controls or a protein assay showing β-catenin-regulated transcription comparable to wild type, limited to the β-catenin binding domain. No such assay or control data are available for NM_001127510.3:c.-11G>C, so BS3 cannot be assessed rather than assigned as benign evidence.

Rule
APC InSiGHT VCEP Version 2.1 BS3: no mRNA aberration in a constitutional RNA assay, with biallelic expression and/or nonsense-mediated decay inhibition for Strong; without those controls for Supporting, or qualifying wild-type-comparable protein function within the β-catenin binding domain.
Evidence considered
  • The APC InSiGHT VCEP Version 2.1 BS3 specification requires no mRNA aberration in a constitutional RNA assay; BS3 Strong additionally requires demonstrated biallelic expression and/or nonsense-mediated decay inhibition, while the protein-assay route is restricted to β-catenin binding-domain variants.
  • The case evidence contains no variant-specific RNA, mRNA, expression-control, nonsense-mediated-decay, or protein functional assay result for NM_001127510.3:c.-11G>C.
  • The ACMG/AMP guideline paper provides general guidance that mRNA assays can evaluate untranslated-region variants, but it reports no benign functional result for this APC variant.
Still missing
  • No constitutional patient-sample RNA assay showing no mRNA aberration is available.
  • No biallelic-expression or nonsense-mediated-decay control data are available for BS3 Strong calibration.
  • No qualifying wild-type-comparable APC protein assay is available.
Sources
cspec ↗PMID:25741868 ↗
BS4 Not assessed: no affected relative lacking APC c.-11G>C or phenotype-point score is documented for non-segregation. Details ▾Hide ▴
Reasoning

The APC VCEP requires an affected member without the variant to score at least 1 phenotype point for strong BS4, or at least 0.5 phenotype points for supporting BS4; no affected non-carrier relative, phenotype score, or family testing result is documented for APC c.-11G>C, so BS4 cannot be assigned.

Rule
APC VCEP Version 2.1: BS4 strong when an affected member without the variant scores >=1 phenotype point or at least two affected non-carriers each score >=0.5 points; supporting when an affected non-carrier scores >=0.5 points.
Evidence considered
  • The APC VCEP Version 2.1 specifies strong BS4 when an affected member without the variant scores at least 1 phenotype point, and supporting BS4 when an affected member without the variant scores at least 0.5 phenotype points.
  • No case-specific affected non-carrier, relative phenotype score, or family testing result is documented in the available evidence.
Still missing
  • Identify affected relatives who tested negative for APC c.-11G>C.
  • Document each non-carrier relative's APC-consistent phenotype and phenotype-point score.
  • Provide reliable genotype and phenotype records for the relatives used to evaluate non-segregation.
Sources
cspec ↗
BP2 Not assessed: no qualifying trans observation or at least 3 unknown-phase observations with different pathogenic APC variants is documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP allows BP2 at Supporting strength when the assessed variant is observed in trans with a (Likely) Pathogenic APC variant, or at least three times with different (Likely) Pathogenic APC variants when phase is unknown. The available case evidence contains no affected-proband observations, co-occurring APC variant, phase determination, or qualifying unknown-phase count, so BP2 cannot be assessed.

Rule
APC VCEP BP2 Supporting: observed in trans with a (Likely) Pathogenic APC variant, or at least 3 times in unknown phase with different (Likely) Pathogenic APC variants.
Evidence considered
  • The APC VCEP BP2 rule requires observation in trans with a (Likely) Pathogenic APC variant or at least three observations in unknown phase with different (Likely) Pathogenic APC variants.
  • The available case evidence documents no proband-level allelic observations, second APC variant, phase, or qualifying observation count for NM_001127510.3:c.-11G>C.
Still missing
  • Affected-proband-level records identifying a second APC variant and its pathogenicity are unavailable.
  • Phase information or at least three qualifying unknown-phase observations with different (Likely) Pathogenic APC variants is unavailable.
Sources
cspec ↗
BP5 Not assessed: no qualifying alternate pathogenic gene finding and no documented colorectal polyposis phenotype are available for BP5. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP limits BP5 to a (Likely) Pathogenic variant in another specified adenomatous-polyposis gene, and only when a colorectal polyposis phenotype is present. The available evidence does not document a colorectal polyposis phenotype or a qualifying alternate pathogenic molecular basis for this patient, so BP5 cannot be assessed.

Rule
BP5 Supporting: only applicable for an alternate genetic basis of the colorectal polyposis phenotype; the APC specification lists qualifying genes and inheritance patterns.
Evidence considered
  • The APC VCEP BP5 rule requires a (Likely) Pathogenic variant in another adenomatous-polyposis gene and applies only when a colorectal polyposis phenotype is present.
  • No alternate pathogenic molecular basis or qualifying phenotype is reported in the available case evidence.
Still missing
  • A documented colorectal polyposis phenotype is unavailable.
  • No qualifying (Likely) Pathogenic variant in another APC-related alternate-basis gene is documented.
Sources
cspec ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.-11G>C is a 5′ UTR synonymous-equivalent change, p.(=), not a specified APC null or canonical splice variant for PVS1. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP framework applies PVS1 to specified loss-of-function and splice-variant categories. NM_001127510.3:c.-11G>C is a 5′ UTR variant with NP_001120982.1:p.(=), is classified as synonymous, and is not a canonical splice-consensus or null variant; therefore PVS1 is not applicable.

Rule
APC InSiGHT VCEP Version 2.1 PVS1 specification and decision tree; no applicable PVS1 category is met.
Evidence considered
  • The APC InSiGHT VCEP Version 2.1 framework provides the governing APC-specific PVS1 guidance and a decision tree for designated null and splice-variant categories.
  • The variant is NM_001127510.3:c.-11G>C, with protein consequence NP_001120982.1:p.(=), consequence class synonymous, and canonical_splice_consensus false.
  • The variant-level assessment states that this change does not fall into the generic PVS1 buckets of nonsense, frameshift, or canonical ±1,2 splice-consensus variants.
Sources
cspec ↗vcep_fig_1_apc_pvs1_decision_tree_2023_10_20pvs1_variant_assessment
PS1 N/ANot applicable: c.-11G>C is a synonymous 5′-UTR variant with p.(=), not a missense or same-nucleotide splice variant. Details ▾Hide ▴
Reasoning

The APC VCEP limits PS1 to missense variants producing the same amino-acid change as an established pathogenic or likely pathogenic variant, or splice variants affecting the same nucleotide. NM_001127510.3:c.-11G>C is annotated as a synonymous 5′-untranslated-region variant with NP_001120982.1:p.(=), so it has no altered amino-acid residue for PS1 comparison and is not a splice-site variant.

Rule
The previously established variant must be pathogenic or likely pathogenic; for missense variants, the assessed variant must result in the same amino-acid change, and for splice variants it must affect the same nucleotide with qualifying splice evidence.
Evidence considered
  • The APC VCEP PS1 rule is restricted to same-amino-acid missense changes or same-nucleotide splice variants.
  • The case normalization is NM_001127510.3:c.-11G>C with NP_001120982.1:p.(=) and synonymous consequence.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PM1 VCEPNot applicable: the APC VCEP designates PM1 as not applicable, and this synonymous variant has no translated residue for domain assessment. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly designates PM1 as not applicable. The variant is also synonymous and has no translated residue to evaluate against a missense critical-domain or hotspot rule.

VCEP rule
PM1 is not applicable under the APC VCEP specification.
Evidence considered
  • The governing APC VCEP criteria list PM1 as Not Applicable.
  • The normalized protein consequence is p.(=), so no amino-acid residue or missense domain position is available.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PM3 VCEPNot applicable: the APC VCEP specifies PM3 is not used because familial adenomatous polyposis is autosomal dominant. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specification explicitly designates PM3 as not applicable because familial adenomatous polyposis due to APC is an autosomal dominant disorder; therefore recessive-disease observations of the assessed variant in trans with a pathogenic variant are not used for this criterion.

VCEP rule
APC VCEP: PM3 is not applicable.
Evidence considered
  • The APC InSiGHT VCEP specification labels PM3 as Not Applicable and identifies the disease context as autosomal dominant familial adenomatous polyposis.
Sources
cspec ↗
PM4 VCEPNot applicable: APC VCEP does not use PM4, and the 5′ UTR change produces p.(=) with no protein length alteration. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP framework states that PM4 is not used because of limited available data. Independently, this variant has no protein length change: it is a 5′ UTR synonymous-equivalent change with NP_001120982.1:p.(=).

VCEP rule
APC InSiGHT VCEP Version 2.1: PM4 not used; no protein length change is present.
Evidence considered
  • The APC InSiGHT VCEP supplementary specifications explicitly state that PM4 is not used because of limited available data.
  • The normalized protein consequence is NP_001120982.1:p.(=), so no in-frame deletion, insertion, or other protein length change is present.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PM5 N/ANot applicable: c.-11G>C is synonymous with p.(=), so no amino-acid residue exists for the APC same-residue missense PM5 rule. Details ▾Hide ▴
Reasoning

The APC VCEP PM5 rule concerns a missense change at an amino-acid residue where another missense variant is established as pathogenic or likely pathogenic, with the specified APC comparator and Grantham-distance requirements. NM_001127510.3:c.-11G>C is synonymous with p.(=), and no amino-acid residue is available for a same-residue missense comparison.

Rule
For APC, PM5 requires a missense variant at a residue where another missense variant is pathogenic or likely pathogenic under APC-specific rules; the assessed variant must also satisfy the specified Grantham-distance requirement.
Evidence considered
  • The APC VCEP PM5 rule requires a missense variant and a qualifying pathogenic or likely pathogenic variant at the same amino-acid residue.
  • The case consequence is synonymous with p.(=), and the comparator assessment found no residue or same-residue missense candidates.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2pm5_candidates
PP2 VCEPNot applicable: the APC VCEP designates PP2 as not applicable, and c.-11G>C is synonymous rather than missense. Details ▾Hide ▴
Reasoning

The APC VCEP explicitly designates PP2 as not applicable. The assessed variant is additionally synonymous rather than a missense variant.

VCEP rule
PP2 is not applicable under the APC VCEP specification.
Evidence considered
  • The governing APC VCEP criteria list PP2 as Not Applicable.
  • The case normalization identifies a synonymous consequence with p.(=).
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP3 N/ANot applicable: the variant is synonymous, whereas PP3 is restricted here to missense or intronic/splice-region variants assessed through the SpliceAI path. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_001127510.3:c.-11G>C is annotated as synonymous (NP_001120982.1:p.(=)), not missense, and is not an intronic or splice-region variant eligible for the SpliceAI path. The APC VCEP specifies PP3 for presumed missense variants assessed for splicing effects and for non-canonical splicing variants; predictor scores must not be evaluated for this out-of-scope criterion.

Rule
APC VCEP PP3: missense variants should not use conservation/evolution computational models; in silico splicing predictors may be used for presumed missense variants to reveal splicing effects, and multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
Evidence considered
  • The case normalization identifies NP_001120982.1:p.(=) and the consequence class as synonymous.
  • The APC Version 2.1 VCEP specifies PP3 for presumed missense variants assessed for splicing effects and for non-canonical splicing variants.
Sources
cspec ↗
PP4 VCEPNot applicable: the APC VCEP explicitly excludes PP4 because phenotype specificity is captured by its PS4 phenotype-point framework. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP marks PP4 as not applicable because phenotype specificity is already captured by its APC-specific PS4 phenotype-point system. Therefore PP4 is not used for this variant under the governing gene-specific framework.

VCEP rule
PP4: Not applicable under the APC InSiGHT VCEP; phenotype or family history is captured by PS4.
Evidence considered
  • The APC VCEP lists PP4 as Not applicable and states that the phenotype or family history is already captured by the PS4 specifications.
Sources
cspec ↗
PP5 VCEPNot applicable: APC excludes PP5, and ClinVar has only a single-laboratory uncertain-significance submission with no expert-panel Pathogenic classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP explicitly marks PP5 as not applicable and states that it is not for use. Independently, the exact ClinVar record is an uncertain-significance single laboratory submission with zero expert-panel submissions, so it does not meet the required exact-variant expert-panel Pathogenic/Likely pathogenic condition.

VCEP rule
PP5: Not applicable under the APC InSiGHT VCEP; the requested expert-panel gate would additionally require an exact-variant ClinVar Expert Panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • The APC VCEP states that PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar variation 918736 has an exact-match single-submitter classification of Uncertain significance, review status criteria provided/single submitter, and zero expert-panel submissions; ordinary laboratory submissions cannot trigger PP5.
Sources
cspec ↗clinvar ↗
BP1 N/ANot applicable: BP1 is a missense criterion, whereas c.-11G>C is synonymous and lies in the 5′ untranslated region with p.(=). Details ▾Hide ▴
Reasoning

The APC VCEP permits BP1 for applicable APC missense variants except those in codons 1021–1035 of the first 15-amino-acid repeat of the β-catenin-binding domain. NM_001127510.3:c.-11G>C is a synonymous 5′-untranslated-region variant with p.(=), not a missense variant, so BP1 does not apply.

Rule
BP1 is applicable to APC except for missense variants in the first 15-amino-acid repeat of the β-catenin-binding domain, codons 1021–1035.
Evidence considered
  • The APC VCEP BP1 rule applies to APC missense variants, with an exception for codons 1021–1035.
  • The assessed variant is synonymous at c.-11 with p.(=), so it is outside the missense scope of BP1.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
BP3 VCEPNot applicable: APC VCEP excludes BP3, and c.-11G>C causes p.(=) without an in-frame protein length change or repeat-region indel. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP Version 2.1 framework designates BP3 as not applicable. The variant is a 5′ UTR synonymous-equivalent change with NP_001120982.1:p.(=), not an in-frame deletion or insertion in a repetitive region.

VCEP rule
APC InSiGHT VCEP Version 2.1: BP3 not applicable.
Evidence considered
  • The APC InSiGHT VCEP criteria list BP3 as not applicable.
  • The normalized consequence is NP_001120982.1:p.(=), and the variant is not an in-frame deletion or insertion affecting protein length.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
BP4 N/ANot applicable: the variant is synonymous and not an intronic/splice-region variant, so BP4's missense or SpliceAI-path scope is not met. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_001127510.3:c.-11G>C is annotated as synonymous (NP_001120982.1:p.(=)), not missense, and is not an intronic or splice-region variant eligible for the SpliceAI path. Although SpliceAI and Pangolin scores are present, the criterion scope is checked first and those predictor results must not be used for this out-of-scope BP4 assessment.

Rule
APC VCEP BP4: for synonymous or intronic variants, multiple in silico splicing predictors should suggest no impact on the gene or gene product; this case-level assessment applies the stated group scope before predictor review.
Evidence considered
  • The case normalization identifies NP_001120982.1:p.(=) and the consequence class as synonymous.
  • The APC Version 2.1 VCEP specifies BP4 for synonymous or intronic variants when multiple in silico splicing predictors suggest no impact, but this group's governing scope limits BP4 evaluation to missense or intronic/splice-region variants via the SpliceAI path.
Sources
cspec ↗
BP6 VCEPNot applicable: APC excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP explicitly marks BP6 as not applicable and states that it is not for use. The exact ClinVar record is also an uncertain-significance single laboratory submission with no expert-panel submission, so it does not meet the required exact-variant expert-panel Benign/Likely benign condition.

VCEP rule
BP6: Not applicable under the APC InSiGHT VCEP; the requested expert-panel gate would additionally require an exact-variant ClinVar Expert Panel Benign or Likely benign classification.
Evidence considered
  • The APC VCEP states that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar variation 918736 has an exact-match single-submitter classification of Uncertain significance and zero expert-panel submissions; ordinary laboratory submissions cannot trigger BP6.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
APC
Transcript
NM_001127510.3
Coding (HGVS c.)
NM_001127510.3:c.-11G>C
Protein (HGVS p.)
NP_001120982.1:p.(=)
GRCh38
chr5:112754880 G>C
GRCh37
chr5:112090577 G>C
Location and type
Exon 3 · synonymous
ClinVar
918736

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +0 bp
0.000
SpliceAI acceptor gainat -7 bp
0.009
SpliceAI donor lossat +0 bp
0.000
SpliceAI donor gainat +214 bp
0.013
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.012

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingMet, Supporting: synonymous variant with SpliceAI maximum delta 0.013 and Pangolin scores 0.012/-0.002 supports no splice impact. Details ▾Hide ▴
Reasoning

BP7 applies because NM_001127510.3:c.-11G>C is annotated as a synonymous variant (NP_001120982.1:p.(=)). The APC VCEP assigns BP7 at Supporting strength when multiple splicing prediction algorithms predict no impact to the splice consensus sequence or creation of a new splice site. SpliceAI reports a maximum delta score of 0.013, with DS_AG 0.009, DS_DG 0.013, DS_AL 0.000, and DS_DL 0.000; Pangolin scores are 0.012 and -0.002. These independent predictor results support no meaningful splice impact, so BP7 is met at Supporting strength.

Rule
APC VCEP 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 or creation of a new splice site.
Evidence considered
  • The variant is annotated as synonymous with protein consequence NP_001120982.1:p.(=).
  • The APC Version 2.1 VCEP BP7 rule requires a synonymous or qualifying intronic variant with multiple splicing predictors indicating no splice impact.
  • SpliceAI reports max delta 0.013: DS_AG 0.009, DS_AL 0.000, DS_DG 0.013, and DS_DL 0.000.
  • Pangolin reports splice scores of 0.012 and -0.002, consistent with no significant predicted splice effect.
Sources
cspec ↗spliceai ↗
PP3 N/ANot applicable: the variant is synonymous, whereas PP3 is restricted here to missense or intronic/splice-region variants assessed through the SpliceAI path. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_001127510.3:c.-11G>C is annotated as synonymous (NP_001120982.1:p.(=)), not missense, and is not an intronic or splice-region variant eligible for the SpliceAI path. The APC VCEP specifies PP3 for presumed missense variants assessed for splicing effects and for non-canonical splicing variants; predictor scores must not be evaluated for this out-of-scope criterion.

Rule
APC VCEP PP3: missense variants should not use conservation/evolution computational models; in silico splicing predictors may be used for presumed missense variants to reveal splicing effects, and multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
Evidence considered
  • The case normalization identifies NP_001120982.1:p.(=) and the consequence class as synonymous.
  • The APC Version 2.1 VCEP specifies PP3 for presumed missense variants assessed for splicing effects and for non-canonical splicing variants.
Sources
cspec ↗
BP4 N/ANot applicable: the variant is synonymous and not an intronic/splice-region variant, so BP4's missense or SpliceAI-path scope is not met. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_001127510.3:c.-11G>C is annotated as synonymous (NP_001120982.1:p.(=)), not missense, and is not an intronic or splice-region variant eligible for the SpliceAI path. Although SpliceAI and Pangolin scores are present, the criterion scope is checked first and those predictor results must not be used for this out-of-scope BP4 assessment.

Rule
APC VCEP BP4: for synonymous or intronic variants, multiple in silico splicing predictors should suggest no impact on the gene or gene product; this case-level assessment applies the stated group scope before predictor review.
Evidence considered
  • The case normalization identifies NP_001120982.1:p.(=) and the consequence class as synonymous.
  • The APC Version 2.1 VCEP specifies BP4 for synonymous or intronic variants when multiple in silico splicing predictors suggest no impact, but this group's governing scope limits BP4 evaluation to missense or intronic/splice-region variants via the SpliceAI path.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Richards S et al. · 2015
    This paper provides general ACMG/AMP guidance on functional evidence, including the use of RNA or cDNA assays for variants in untranslated regions, but it reports no APC-specific functional assay, observation, or conclusion for NM_001127510.3:c.-11G>C.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    Assays that assess the impact of variants at the mRNA level can be highly informative when evaluating the effects of variants at splice junctions and within coding sequences, untranslated regions, as well as deeper intronic regions (e.g. mRNA stability, processing or translation).

    Proposed Criteria for Interpretation of Sequence Variants, PS3 BS3 Functional studies

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    This practice guideline does not mention APC c.-11G>C and provides no variant-specific segregation, de novo, parental-testing, or non-segregation evidence. It describes clinical referral findings associated with familial adenomatous polyposis but cannot establish segregation evidence for this variant.
    Does not name this variant
    PMID 25394175 ↗
    Quoted passage
    • ≥ 10 cumulative adenomatous colon polyps in the same person FAP, OMIM 175100; MAP, OMIM 608456

    Table 1, "Colorectal polyposis, adenomatous"

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.013 Open source ↗
ClinVar 1 Uncertain significance Open source ↗
COSMIC Captured COSMIC 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 918736)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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 has not previously been reported in somatic cancers (COSMIC).