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APCc.6873A>TUncertain significance
Print report
Variant interpretation report

APC c.6873A>T, p.(Gln2291His)

NM_001127510.3:c.6873A>T NP_001120982.1:p.(Gln2291His) Missense · exon 17 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: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Supporting
BP1 · supporting

Met, supporting: codon 2291 lies outside the VCEP's BP1 exception at codons 1021-1035.

Recorded classification: Uncertain significance

VUS: BP1 supporting is the only met criterion, and no APC VCEP Version 2.1 pathogenic or benign combination rule is satisfied.

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
374 / 1,613,966 alleles

gnomAD v4.1: 374 / 1,613,966 alleles. Recorded AF 0.000231727. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000145204; MAF= 0.01452%, 41/282362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000294972; MAF= 0.02950%, 38/128826 alleles, homozygotes = 0); grpmax FAF= 0.00022755.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.147 recorded score

Recorded REVEL score: 0.147. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
20 reported laboratory submissions

14 Likely benign · 4 Uncertain significance · 1 Benign · 1 Likely Benign.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. APC, a tumor suppressor involved in WNT signaling, is recurrently altered in colorectal cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV105854020, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 1 met · 2 not met · 14 not assessed · 11 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

PS1 is not met because no same-amino-acid established APC missense comparator is documented.

PM1 and PP2 are not applicable under the APC InSiGHT VCEP specification.

PM5 remains not assessed because no same-residue comparator was retrieved and the comparator harvest reported an HTTP 429 failure.

BP1 is met at supporting strength because codon 2291 is outside the APC VCEP exception at codons 1021-1035.

No case-specific parental testing, de novo, segregation, or non-segregation observations were available to adjudicate PS2, PM6, PP1, or BS4 under the APC InSiGHT VCEP specification.

The APC InSiGHT VCEP is the governing framework and takes precedence over generic ACMG criteria.

PS4 could not be assessed because no usable exact-variant phenotype-point or case-control enrichment data were documented.

PP4, PP5, and BP6 are explicitly not applicable under the APC VCEP.

BP5 remains not assessed because the required alternate pathogenic polyposis-gene finding and colorectal polyposis phenotype were not documented.

The governing APC InSiGHT VCEP requires gnomAD v2.1.1 non-cancer data for BA1, BS1, and PM2, and permits that dataset for BS2 homozygote searches; those required subset data are absent.

Combined all-comers gnomAD data are reported for transparency but are not substituted for the VCEP-specified non-cancer source.

Met · 1

BP1 SupportingMet, supporting: codon 2291 lies outside the VCEP's BP1 exception at codons 1021-1035. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP states that BP1 is applicable to APC missense variants except those located in the first 15-amino-acid repeat of the beta-catenin-binding domain, defined as codons 1021-1035. The assessed missense variant is p.(Gln2291His) at codon 2291, outside the exception, so BP1 applies at supporting strength.

Rule
BP1 applies at supporting strength to APC missense variants outside codons 1021-1035, the first 15-amino-acid repeat of the beta-catenin-binding domain.
Evidence considered
  • The APC InSiGHT VCEP BP1 rule applies to APC missense variants except those in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.
  • The assessed variant is p.(Gln2291His) at codon 2291, which is outside codons 1021-1035.
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

PS1 Not met: p.(Gln2291His) has no documented same-amino-acid APC comparator among the VCEP's two established missense variants. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits PS1 for a missense variant producing the same amino-acid change as a previously established pathogenic or likely pathogenic APC variant. The assessed variant is NP_001120982.1:p.(Gln2291His), whereas the VCEP identifies only p.(Asn1026Ser) and p.(Ser1028Arg) as established likely pathogenic APC missense variants; no same-amino-acid comparator is present in the reviewed case evidence.

Rule
For APC missense variants, apply PS1 when the assessed variant produces the same amino-acid change as a previously established pathogenic or likely pathogenic APC variant; the VCEP lists p.(Asn1026Ser) and p.(Ser1028Arg) as the only established likely pathogenic missense variants.
Evidence considered
  • The APC InSiGHT VCEP rule states that PS1 applies to the same amino-acid change as a previously established pathogenic or likely pathogenic missense variant.
  • The assessed protein change is p.(Gln2291His) at residue 2291, while the VCEP lists only p.(Asn1026Ser) and p.(Ser1028Arg) as the currently established likely pathogenic APC missense variants; no same-amino-acid match is shown.
Sources
cspec ↗
PP3 Not met: SpliceAI max delta 0.00 and Pangolin scores 0.001/-0.006 do not support the APC VCEP's deleterious-splicing requirement. Details ▾Hide ▴
Reasoning

The APC ClinGen InSiGHT VCEP specification permits PP3 for missense variants only when multiple in silico splicing predictors support a deleterious effect. This is a missense variant, so PP3 is in scope, but the available splice predictors do not support a deleterious splice effect: SpliceAI max delta is 0.00, with Pangolin scores of 0.001 and -0.006. Therefore PP3 is not met. Missense conservation predictors are not used under the governing APC specification.

Rule
APC VCEP PP3: multiple in silico splicing predictors must support a deleterious effect; missense conservation/evolutionary prediction models are not used.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification states that PP3 for missense variants requires in silico splicing predictors to reveal possible splicing effects and that multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
  • SpliceAI reports a max delta score of 0.00; Pangolin reports scores of 0.001 and -0.006 for this variant, providing no concordant deleterious splice prediction.
  • The variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His), so PP3 is evaluated rather than treated as out of scope.
Sources
cspec ↗spliceai ↗

Not assessed · 14 · no assessment recorded

PS2 Not assessed: no proband-level parental testing or confirmed maternity and paternity evidence is documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PS2 using de novo scores: at least 4 scores for Very Strong, 2–3.5 for Strong, and 1–1.5 for Moderate. The available case evidence does not document a proband-level de novo observation, confirmed maternity and paternity, parental testing results, or a phenotype-based de novo score for NM_001127510.3:c.6873A>T (p.Gln2291His). Therefore PS2 cannot be assessed.

Rule
APC InSiGHT VCEP v2.1 PS2: ≥4 de novo scores = Very Strong; 2–3.5 = Strong; 1–1.5 = Moderate.
Evidence considered
  • The APC InSiGHT VCEP PS2 rule assigns de novo scores from phenotype points: a proband with at least 1 phenotype point contributes 2 points when parental relationships are confirmed or 1 point when they are unconfirmed; a proband with 0.5 phenotype points contributes 1 or 0.5 points, respectively.
  • No case-specific proband phenotype, parental testing, maternity, paternity, or de novo score was documented in the reviewed evidence.
Still missing
  • Proband-level variant results and phenotype details
  • Parental testing results confirming or excluding the variant in both biological parents
  • Confirmed maternity and paternity
  • APC VCEP phenotype points needed to calculate a de novo score
Sources
cspec ↗
PS3 Not assessed: no variant-specific validated damaging assay was available, and the APC protein-assay route is restricted to codons 959-2129 while this variant affects codon 2291. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT APC specification is governing. It permits PS3 for damaging RNA findings, including premature stop codon or specified exon skipping with transcript loss, or for protein assays showing increased beta-catenin-regulated transcription or decreased beta-catenin binding by surface plasmon resonance, restricted to the beta-catenin binding domain at codons 959-2129. This variant is a missense change, p.(Gln2291His), at codon 2291, outside that domain. The case evidence contains no variant-specific validated RNA assay, transcript quantification, protein assay, or reproducible clinical-laboratory functional result demonstrating a damaging effect. PS3 cannot therefore be assigned at any strength.

Rule
**RNA assays** show 1. a premature stop codon OR 2. inframe skipping of exon 13 or 14 **AND** the absence of full-length transcript. The APC-specific Supporting rule also permits RNA evidence of specified exon skipping or alternative-transcript over-expression, or protein assays showing increased beta-catenin regulated transcription activity and/or decreased binding to beta-catenin by surface plasmon resonance, only for variants within the beta-catenin binding domain (codons 959-2129).
Evidence considered
  • The APC-specific PS3 rule allows Very Strong, Strong, Moderate, or Supporting evidence only from specified damaging RNA findings or from protein assays showing increased beta-catenin-regulated transcription and/or decreased beta-catenin binding by surface plasmon resonance.
  • The APC protein-assay PS3 route is limited to the beta-catenin binding domain, defined by the VCEP as codons 959-2129; the variant is p.(Gln2291His) at codon 2291.
  • The available case evidence does not provide a variant-specific RNA assay, transcript measurement, protein assay, assay controls, or reproducible clinical-laboratory functional result for c.6873A>T.
Still missing
  • A variant-specific validated functional study is needed, with appropriate wild-type and damaging controls and assay results demonstrating loss of APC function.
  • For an RNA-based route, transcript identity and quantitative full-length transcript results would be needed; for a protein route, an assay validated for the codon 2291 region would be needed.
Sources
cspec ↗
PS4 Not assessed: no usable phenotype-point total, case-control enrichment estimate, or exact-variant affected-individual evidence is available for PS4. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP assigns PS4 from phenotype points: >=16 points is Very Strong, 4-15.5 Strong, 2-3.5 Moderate, and 1-1.5 Supporting, with phenotype points curated using Table 1. The available evidence does not document the variant in affected individuals with sufficient phenotype-point details, a case-control enrichment estimate, or a statistically supported comparison with controls. The literature extracts for PMID:22703879, PMID:22855150, PMID:23429431, PMID:23788249, PMID:24033266, PMID:24310308, PMID:25356965, and PMID:25479140 do not identify this exact APC variant or provide usable variant-specific PS4 data. Therefore PS4 cannot be assessed rather than treated as absent.

Rule
PS4: >=16 phenotype points = Very Strong; 4-15.5 = Strong; 2-3.5 = Moderate; 1-1.5 = Supporting. For phenotype-point curation see APC VCEP Table 1.
Evidence considered
  • The APC InSiGHT VCEP specifies PS4 as >=16 phenotype points for Very Strong, 4-15.5 for Strong, 2-3.5 for Moderate, and 1-1.5 for Supporting; phenotype points are curated from Table 1.
  • No exact-variant phenotype-point total, case-control odds ratio/relative risk, confidence interval, or statistically supported enrichment result is documented.
  • PMID:22703879 reports APC as a gene analyzed in 572 exome-sequenced participants but does not mention APC c.6873A>T or p.(Q2291H).
  • PMID:22855150, PMID:23429431, PMID:23788249, PMID:24310308, PMID:25356965, and PMID:25479140 do not provide exact-variant clinical or case-control evidence for APC c.6873A>T.
Still missing
  • Exact-variant affected-case reports with APC VCEP Table 1 phenotype details and deduplicated proband counts are needed.
  • A case-control odds ratio or relative risk with a confidence interval, if available, is needed for direct enrichment assessment.
Sources
cspec ↗vcep_table_1_262PMID:22703879 ↗PMID:22855150 ↗PMID:23429431 ↗PMID:23788249 ↗PMID:24033266 ↗PMID:24310308 ↗PMID:25356965 ↗PMID:25479140 ↗
PM2 Not assessed: required gnomAD v2.1.1 non-cancer AF is unavailable; all-comers AFs are 0.000145204 and 0.000231727, above the VCEP PM2 threshold. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies the total population from the gnomAD v2.1.1 non-cancer dataset for PM2 and defines PM2 Supporting as AF <= 0.000003 when allele count is >1 or AF < 0.00001 when allele count is <=1. The available combined all-comers gnomAD v2.1 has AF 0.000145204 with allele count 41 and gnomAD v4.1 has AF 0.000231727 with allele count 374; neither satisfies the threshold, but the required non-cancer dataset is unavailable.

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. Use the total population from the non-cancer dataset from gnomAD (v2.1.1).
Evidence considered
  • The APC InSiGHT VCEP Version 2.1 specifies the total population from the gnomAD v2.1.1 non-cancer dataset and defines PM2 Supporting as AF <= 0.000003 when allele count is >1 or AF < 0.00001 when allele count is <=1.
  • Available combined all-comers data show gnomAD v2.1 AF 0.000145204 with allele count 41 and gnomAD v4.1 AF 0.000231727 with allele count 374; both exceed the applicable threshold, but neither is the required VCEP non-cancer source.
Still missing
  • GnomAD v2.1.1 non-cancer total AF and allele count required by the APC VCEP are not present.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 Not assessed: zero p.Gln2291 comparator candidates were retrieved, but the comparator search recorded an HTTP 429 failure. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits PM5 when a different missense variant at the same amino-acid residue is established as likely pathogenic or pathogenic under APC-specific modifications, with the assessed variant meeting the required Grantham-distance comparison. The assessed variant is p.(Gln2291His), but the reviewed PM5 candidate file reports zero same-residue candidates and zero expert-panel or non-expert-majority pathogenic/likely pathogenic comparators; its comparator harvest also records an HTTP 429 failure. Therefore, the available evidence does not establish PM5, but the failed retrieval prevents a definitive not-met conclusion.

Rule
For APC missense variants, PM5 requires a different missense change at the same residue established as pathogenic or likely pathogenic under APC-specific modifications; the assessed variant must have an equal or higher Grantham distance than the comparator.
Evidence considered
  • The APC InSiGHT VCEP PM5 rule requires a different missense variant at the same amino-acid residue to be pathogenic or likely pathogenic under APC-specific modifications; the assessed Grantham distance must be equal to or greater than that of the comparator.
  • The reviewed PM5 candidate file reports zero same-residue candidates, zero expert-panel pathogenic/likely pathogenic candidates, and zero non-expert-majority pathogenic/likely pathogenic candidates, while also recording an HTTP 429 candidate-harvest failure.
Still missing
  • A validated ClinVar or literature search for pathogenic or likely pathogenic APC missense variants at residue 2291 is still needed, including the required Grantham-distance comparison.
Sources
cspec ↗pm5_candidates
PM6 Not assessed: no assumed-de-novo observation or de novo score is documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PM6 using de novo scores when maternity and paternity are not confirmed: 2–3.5 scores support Strong, 1–1.5 support Moderate, and 0.5 supports Supporting. The available case evidence does not document an assumed-de-novo observation, parental testing, relationship status, or a phenotype-based de novo score for NM_001127510.3:c.6873A>T (p.Gln2291His). Therefore PM6 cannot be assessed.

Rule
APC InSiGHT VCEP v2.1 PM6: 2–3.5 de novo scores = Strong; 1–1.5 = Moderate; 0.5 = Supporting.
Evidence considered
  • The APC InSiGHT VCEP PM6 rule assigns 2–3.5 de novo scores as Strong, 1–1.5 as Moderate, and 0.5 as Supporting when parental relationships are unconfirmed.
  • No case-specific assumed-de-novo observation, parental relationship information, or de novo score was documented in the reviewed evidence.
Still missing
  • Evidence that the variant was observed in a proband with an APC-consistent phenotype
  • Parental testing or documentation that maternity and paternity were unconfirmed
  • APC VCEP phenotype points needed to calculate a de novo score
Sources
cspec ↗
PP1 Not assessed: no affected relatives, informative pedigree, or countable segregating meioses are documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies PP1 as 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. The available case evidence contains no informative family pedigree, affected relatives, variant-positive relatives, or countable segregating meioses. Therefore PP1 cannot be assessed.

Rule
APC InSiGHT VCEP v2.1 PP1: 3–4 meioses in at least 1 family = Supporting; 5–6 meioses in at least 1 family = Moderate; ≥7 meioses in ≥2 families = Strong.
Evidence considered
  • The APC InSiGHT VCEP PP1 rule requires 3–4 segregating meioses for Supporting, 5–6 for Moderate, or at least 7 meioses in at least 2 families for Strong.
  • No family segregation observations or informative meioses were documented in the reviewed evidence.
Still missing
  • Informative family pedigree
  • Affected relatives with phenotype details
  • Variant status in relatives
  • Number of informative segregating meioses and families
Sources
cspec ↗
BA1 Not assessed: the required gnomAD v2.1.1 non-cancer Popmax AF is unavailable; available all-comers grpmax FAFs are 0.00022755 and 0.00027477 versus 0.001. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies the gnomAD v2.1.1 non-cancer dataset for BA1 and requires gnomAD Popmax Filtering AF >= 0.001. The case contains only combined all-comers gnomAD totals: gnomAD v2.1 grpmax FAF 0.00022755 and gnomAD v4.1 grpmax FAF 0.00027477, both below the VCEP threshold, but the required non-cancer dataset is not available for the governing assessment.

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 Version 2.1 specifies the non-cancer gnomAD v2.1.1 dataset for BA1 and sets the Popmax Filtering AF threshold at >= 0.001.
  • Available combined all-comers data show gnomAD v2.1 grpmax FAF 0.00022755 and gnomAD v4.1 grpmax FAF 0.00027477, neither reaching 0.001; these cannot replace the VCEP-specified non-cancer dataset.
Still missing
  • GnomAD v2.1.1 non-cancer Popmax Filtering AF required by the APC VCEP is not present.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not assessed: the required gnomAD v2.1.1 non-cancer Popmax AF is unavailable; available all-comers grpmax FAFs exceed the 0.00001 threshold but are not the specified source. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies the gnomAD v2.1.1 non-cancer dataset for BS1 and requires gnomAD Popmax Filtering AF >= 0.00001. The case contains only combined all-comers gnomAD totals: gnomAD v2.1 grpmax FAF 0.00022755 and gnomAD v4.1 grpmax FAF 0.00027477, both above the VCEP threshold, but the required non-cancer dataset is not available for the governing assessment.

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 Version 2.1 specifies the non-cancer gnomAD v2.1.1 dataset for BS1 and sets the Popmax Filtering AF threshold at >= 0.00001.
  • Available combined all-comers data show gnomAD v2.1 grpmax FAF 0.00022755 and gnomAD v4.1 grpmax FAF 0.00027477, both above 0.00001; these cannot replace the VCEP-specified non-cancer dataset.
Still missing
  • Gnomad v2.1.1 non-cancer Popmax Filtering AF required by the APC VCEP is not present.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 Not assessed: available all-comers gnomAD v2.1 and v4.1 report zero homozygotes, but the VCEP-specified non-cancer homozygote dataset is unavailable. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP permits the gnomAD v2.1.1 non-cancer dataset to search for homozygous individuals and requires either at least 10 healthy-individual points or at least 2 homozygous observations for strong BS2. The available combined gnomAD v2.1 and v4.1 data report zero homozygotes, but no VCEP-specified non-cancer homozygote count or qualifying healthy-individual observations is available.

Rule
Strong: >= 10 points for healthy individuals OR >= 2 times in homozygous 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. Supporting: >= 3 points for healthy individuals.
Evidence considered
  • The APC InSiGHT VCEP states that the gnomAD v2.1.1 non-cancer dataset may be used to search for homozygous individuals and defines strong BS2 as at least 10 healthy-individual points or at least 2 homozygous observations.
  • Available combined all-comers gnomAD v2.1 and v4.1 each report homozygotes = 0, but the required non-cancer homozygote dataset and qualifying healthy-individual phenotype information are absent.
Still missing
  • GnomAD v2.1.1 non-cancer homozygote count required by the APC VCEP is not present.
  • No qualifying healthy-individual point data are available.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no variant-specific benign functional assay was available, and the APC protein-assay route is restricted to codons 959-2129 while this variant affects codon 2291. Details ▾Hide ▴
Reasoning

The ClinGen InSiGHT APC specification is governing. BS3 Strong requires an RNA assay of a synonymous or intronic variant in a constitutional patient sample showing no mRNA aberration together with demonstrated biallelic expression or nonsense-mediated decay inhibition. BS3 Supporting permits that RNA evidence without those additional controls, or a protein assay showing retention of beta-catenin-regulated transcription comparable to wild type, but only for variants within the beta-catenin binding domain at codons 959-2129. This variant is a missense change at codon 2291, and the case evidence contains no variant-specific benign functional assay. BS3 is therefore not assessed.

Rule
**RNA assay** of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration **AND** biallelic expression is shown and/or nonsense-mediated decay inhibition was used. The APC-specific Supporting rule also permits a protein assay showing retention of beta-catenin regulated transcription activity comparable to wild-type, only for variants within the beta-catenin binding domain (codons 959-2129).
Evidence considered
  • The APC-specific BS3 Strong rule requires a constitutional RNA assay showing no mRNA aberration plus demonstrated biallelic expression and/or nonsense-mediated decay inhibition.
  • The APC-specific BS3 Supporting rule permits retention of beta-catenin-regulated transcription comparable to wild type in a protein assay only for variants within codons 959-2129.
  • The variant is missense p.(Gln2291His) at codon 2291, outside the specified protein-assay domain, and no variant-specific benign RNA or protein assay with controls is available in the case evidence.
Still missing
  • A variant-specific benign functional study with appropriate controls is needed; the VCEP RNA routes are defined for synonymous or intronic variants and the protein route is restricted to codons 959-2129.
Sources
cspec ↗
BS4 Not assessed: no affected, variant-negative relative with an APC phenotype score is documented. Details ▾Hide ▴
Reasoning

The APC InSiGHT VCEP specifies BS4 as Supporting when an affected member without the variant scores at least 0.5 phenotype points, and Strong when one affected member scores at least 1 point or two affected members each score at least 0.5 points. The available case evidence does not document affected relatives lacking the variant, their phenotype points, or a family pedigree. Therefore BS4 cannot be assessed.

Rule
APC InSiGHT VCEP v2.1 BS4: affected member without the variant with ≥0.5 phenotype points = Supporting; one with ≥1 point or two each with ≥0.5 points = Strong.
Evidence considered
  • The APC InSiGHT VCEP BS4 rule requires one affected variant-negative member with at least 0.5 phenotype points for Supporting, or one with at least 1 point or two each with at least 0.5 points for Strong.
  • No affected variant-negative relatives, phenotype points, or family segregation data were documented in the reviewed evidence.
Still missing
  • Affected relative(s) who test negative for the variant
  • APC phenotype details and points for each variant-negative affected relative
  • Informative family pedigree
Sources
cspec ↗
BP2 Not assessed: no documented phase, affected-proband observation, or second (Likely) Pathogenic APC variant is available for this case. Details ▾Hide ▴
Reasoning

The applicable APC VCEP specifies BP2 at Supporting strength when the variant is observed in trans with a (Likely) Pathogenic APC variant, or at least three times in an unknown phase with different (Likely) Pathogenic APC variants. The available case evidence documents no affected-proband observation with a second APC variant, no pathogenic partner variant, and no phase information; therefore BP2 cannot be assessed.

Rule
Observed in trans with a (Likely) Pathogenic APC variant OR ≥ 3 times in an unknown phase with different (Likely) Pathogenic APC variants.
Evidence considered
  • The APC VCEP version 2.1 BP2 rule is Supporting for a variant observed in trans with a (Likely) Pathogenic APC variant, or for at least three observations in unknown phase with different (Likely) Pathogenic APC variants.
  • No case-specific documentation was provided for phase, cis/trans status, an affected proband carrying a second APC variant, or three independent unknown-phase observations with different (Likely) Pathogenic APC variants.
Still missing
  • Affected-proband or clinical-case observations involving NM_001127510.3:c.6873A>T are needed.
  • A second (Likely) Pathogenic APC variant and its phase relative to c.6873A>T must be documented, or at least three independent unknown-phase observations with different (Likely) Pathogenic APC variants must be established.
Sources
cspec ↗
BP5 Not assessed: no documented alternate pathogenic polyposis-gene finding with the required colorectal polyposis phenotype establishes BP5. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP defines BP5 as Supporting only when a (Likely) Pathogenic variant in another adenomatous polyposis gene provides an alternate genetic basis, and only when a colorectal polyposis phenotype is present. The available case evidence does not document such an alternate pathogenic finding together with the required phenotype. The variant's ClinVar submissions and population data do not establish BP5. Therefore BP5 is not assessed because the required clinical and molecular facts are not available, rather than being inferred from the variant's benign-leaning aggregate classification.

Rule
BP5 Supporting: a (Likely) Pathogenic variant in another qualifying adenomatous polyposis gene, with a colorectal polyposis phenotype present.
Evidence considered
  • The APC InSiGHT VCEP BP5 instruction requires a (Likely) Pathogenic variant in another adenomatous polyposis gene and says the rule applies only when a colorectal polyposis phenotype is present.
  • No qualifying alternate-gene pathogenic finding and no sufficient colorectal polyposis phenotype documentation are available in the reviewed case evidence.
Still missing
  • A documented colorectal polyposis phenotype is needed.
  • A confirmed (Likely) Pathogenic variant in another qualifying adenomatous polyposis gene is needed.
Sources
cspec ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.6873A>T is a missense change producing p.(Gln2291His), not an APC null or canonical splice variant covered by PVS1. Details ▾Hide ▴
Reasoning

The APC VCEP framework applies PVS1 to null variants in APC, with strength assigned by its PVS1 decision tree. NM_001127510.3:c.6873A>T is a missense variant predicted to produce p.(Gln2291His), not a nonsense, frameshift, or canonical splice variant; therefore PVS1 is not applicable. No PVS1 strength tier is assigned.

Rule
APC VCEP PVS1: null variant in a gene where loss of function is a known disease mechanism, classified according to the modified APC PVS1 decision tree; missense variants are outside this criterion.
Evidence considered
  • The APC InSiGHT VCEP specification states that PVS1 is for null variants in APC, with strength determined using the modified APC PVS1 decision tree.
  • The variant consequence is missense: NM_001127510.3:c.6873A>T, NP_001120982.1:p.(Gln2291His); no premature termination or canonical splice alteration is present.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PM1 VCEPNot applicable: the APC VCEP marks PM1 not applicable and supplies no authoritative domain-table entry for this gene. Details ▾Hide ▴
Reasoning

The governing APC InSiGHT VCEP marks PM1 as not applicable. The case vcep_materials domain_tables object is empty, so there is no authoritative APC domain-table entry in this case to support PM1; no domain boundaries are re-derived from generic or flattened text.

VCEP rule
PM1 is not applicable for APC under the governing InSiGHT VCEP specification.
Evidence considered
  • The APC InSiGHT VCEP specification explicitly marks PM1 as Not Applicable.
  • The case's vcep_materials domain_tables object is empty, so no authoritative approved APC critical-domain list is available for residue 2291.
Sources
cspec ↗
PM3 VCEPNot applicable: the APC VCEP version 2.1 explicitly designates PM3 as not applicable for APC. Details ▾Hide ▴
Reasoning

The applicable ClinGen InSiGHT APC VCEP specification, version 2.1, explicitly designates PM3 as not applicable for APC. Therefore, PM3 is not evaluated from the absence or presence of phase, biallelic, or compound-heterozygous observations in this case.

VCEP rule
Not Applicable
Evidence considered
  • The ClinGen InSiGHT APC VCEP specification version 2.1 lists PM3 as Not Applicable.
  • The APC VCEP rule is applicable to this APC variant and takes precedence over generic ACMG/AMP PM3 guidance.
Sources
cspec ↗
PM4 VCEPNot applicable: APC VCEP designates PM4 unused, and c.6873A>T causes a missense substitution without a protein-length change. Details ▾Hide ▴
Reasoning

The APC VCEP specification explicitly designates PM4 as not applicable because of limited available data. This variant is also a missense substitution, p.(Gln2291His), rather than an in-frame deletion, insertion, or other protein-length change to which generic PM4 would apply.

VCEP rule
APC VCEP PM4: not applicable; the specification states that PM4 is not used due to limited available data.
Evidence considered
  • The APC InSiGHT VCEP supplementary specification lists PM4 as not used due to limited available data.
  • The normalized protein consequence is p.(Gln2291His), an amino-acid substitution with no in-frame deletion, insertion, or protein-length change.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP2 VCEPNot applicable: the APC VCEP excludes PP2 because missense variants are not a frequent disease mechanism in APC. Details ▾Hide ▴
Reasoning

The governing APC InSiGHT VCEP marks PP2 as not applicable because missense variants are not a frequent disease mechanism for APC in the specified framework.

VCEP rule
PP2 is not applicable to APC under the governing InSiGHT VCEP specification.
Evidence considered
  • The APC InSiGHT VCEP specification explicitly marks PP2 as Not Applicable and states that missense variants are not a frequent disease mechanism for APC.
Sources
cspec ↗
PP4 VCEPNot applicable: the APC VCEP explicitly excludes PP4 because phenotype evidence is captured through its PS4 phenotype-point system. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP marks PP4 as not applicable. Its specification states that the patient's phenotype or family history criterion is already captured by the PS4 phenotype-point system. No generic PP4 assessment is substituted when an applicable VCEP specification excludes the criterion.

VCEP rule
PP4: Not applicable under the APC InSiGHT VCEP; phenotype evidence is captured by PS4.
Evidence considered
  • The APC InSiGHT VCEP lists PP4 as Not applicable and provides no strength rule for it.
Sources
cspec ↗
PP5 VCEPNot applicable: the APC VCEP excludes PP5, and ClinVar shows no exact-variant expert-panel classification for this variant. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP marks PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The ClinVar record is a single-submitter record with no expert-panel submissions, so it would not independently satisfy the exact-variant expert-panel requirement either.

VCEP rule
PP5: Not applicable under the APC InSiGHT VCEP; an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification would be required by the requested adjudication rule, but none is present.
Evidence considered
  • The APC InSiGHT VCEP states that PP5 is Not Applicable for this VCEP and is not for use.
  • ClinVar lists this variant as Likely benign with review status criteria provided, single submitter; expert-panel submissions are absent.
  • Ordinary laboratory submissions and aggregate ClinVar labels are not eligible to trigger PP5.
Sources
cspec ↗clinvar ↗
BP3 VCEPNot applicable: APC VCEP designates BP3 unused, and p.(Gln2291His) is not an in-frame indel in a repetitive region. Details ▾Hide ▴
Reasoning

The APC VCEP specification explicitly designates BP3 as not applicable. In addition, this variant is a missense substitution rather than an in-frame deletion or insertion in a repetitive region, so the generic BP3 concept does not apply.

VCEP rule
APC VCEP BP3: not applicable.
Evidence considered
  • The APC InSiGHT VCEP specification lists BP3 as not applicable.
  • The variant produces the missense substitution p.(Gln2291His), not an in-frame deletion or insertion in a repetitive region.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for this missense variant, p.(Gln2291His). Details ▾Hide ▴
Reasoning

The variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His). The governing APC ClinGen InSiGHT VCEP specification explicitly states that BP4 is not applicable to missense variants; therefore BP4 is not evaluated, regardless of the available computational scores.

Rule
APC VCEP BP4: missense variants are not applicable.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification explicitly states: BP4 is not applicable to missense variants.
  • Variant consequence is missense: NM_001127510.3:c.6873A>T produces p.(Gln2291His).
Sources
cspec ↗
BP6 VCEPNot applicable: the APC VCEP excludes BP6, and no exact-variant ClinVar expert-panel benign or likely-benign classification is present. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP marks BP6 as not applicable and states that it is not for use. In addition, the ClinVar record has no expert-panel submissions; its single-submitter and aggregate benign or likely-benign laboratory labels cannot trigger BP6 under the requested exact-variant expert-panel rule.

VCEP rule
BP6: Not applicable under the APC InSiGHT VCEP; an exact-variant ClinVar expert-panel Benign or Likely benign classification would be required by the requested adjudication rule, but none is present.
Evidence considered
  • The APC InSiGHT VCEP states that BP6 is Not Applicable for this VCEP and is not for use.
  • ClinVar shows no expert-panel submissions and reports only single-submitter laboratory classifications, including Likely benign and Benign.
  • Ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions are not eligible to trigger BP6.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or qualifying intronic variants, whereas this variant is missense, p.(Gln2291His). Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. This variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His), so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 applies only to synonymous or qualifying intronic variants; this missense variant is out of scope.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification defines BP7 for synonymous or qualifying intronic variants with no predicted splice impact.
  • Variant consequence is missense: NM_001127510.3:c.6873A>T produces p.(Gln2291His).
Sources
cspec ↗

Identifiers

Gene
APC
Transcript
NM_001127510.3
Coding (HGVS c.)
NM_001127510.3:c.6873A>T
Protein (HGVS p.)
NP_001120982.1:p.(Gln2291His)
GRCh38
chr5:112842467 A>T
GRCh37
chr5:112178164 A>T
Location and type
Exon 17 · missense
ClinVar
3305207, 1756303, 390267, 41534
COSMIC
COSV105854020

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 v4.1 374 / 1,613,966 alleles AF 0.000232 · 0 homozygotes · FAF 0.000275
gnomAD v2.1 41 / 282,362 alleles AF 0.000145 · 0 homozygotes · FAF 0.000228
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00023 · 374 / 1,613,966 alleles · 0 hom · FAF 0.00027
European (non-Finnish)355 / 1,179,916 0.0003
Remaining individuals12 / 62,498 0.00019
Admixed American3 / 60,002 5e-05
European (Finnish)2 / 64,030 3.1e-05
East Asian1 / 44,858 2.2e-05
African/African American1 / 75,016 1.3e-05
0 alternate alleles recorded in 4 other groups: Amish, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.00015 · 41 / 282,362 alleles · 0 hom · FAF 0.00023
European (non-Finnish)38 / 128,826 0.00029
Remaining individuals1 / 7,210 0.00014
European (Finnish)1 / 25,088 4e-05
Admixed American1 / 35,388 2.8e-05
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, East Asian, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000231727; MAF= 0.02317%, 374/1613966 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000300869; MAF= 0.03009%, 355/1179916 alleles, homozygotes = 0); grpmax FAF= 0.00027477.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000145204; MAF= 0.01452%, 41/282362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000294972; MAF= 0.02950%, 38/128826 alleles, homozygotes = 0); grpmax FAF= 0.00022755.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.001

Other predictors

REVEL
0.147
BayesDel
-0.362

How the predictions were used

PP3 Not met: SpliceAI max delta 0.00 and Pangolin scores 0.001/-0.006 do not support the APC VCEP's deleterious-splicing requirement. Details ▾Hide ▴
Reasoning

The APC ClinGen InSiGHT VCEP specification permits PP3 for missense variants only when multiple in silico splicing predictors support a deleterious effect. This is a missense variant, so PP3 is in scope, but the available splice predictors do not support a deleterious splice effect: SpliceAI max delta is 0.00, with Pangolin scores of 0.001 and -0.006. Therefore PP3 is not met. Missense conservation predictors are not used under the governing APC specification.

Rule
APC VCEP PP3: multiple in silico splicing predictors must support a deleterious effect; missense conservation/evolutionary prediction models are not used.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification states that PP3 for missense variants requires in silico splicing predictors to reveal possible splicing effects and that multiple in silico splicing predictors support a deleterious effect for non-canonical splicing variants.
  • SpliceAI reports a max delta score of 0.00; Pangolin reports scores of 0.001 and -0.006 for this variant, providing no concordant deleterious splice prediction.
  • The variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His), so PP3 is evaluated rather than treated as out of scope.
Sources
cspec ↗spliceai ↗
BP4 N/ANot applicable: the APC VCEP explicitly excludes BP4 for this missense variant, p.(Gln2291His). Details ▾Hide ▴
Reasoning

The variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His). The governing APC ClinGen InSiGHT VCEP specification explicitly states that BP4 is not applicable to missense variants; therefore BP4 is not evaluated, regardless of the available computational scores.

Rule
APC VCEP BP4: missense variants are not applicable.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification explicitly states: BP4 is not applicable to missense variants.
  • Variant consequence is missense: NM_001127510.3:c.6873A>T produces p.(Gln2291His).
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or qualifying intronic variants, whereas this variant is missense, p.(Gln2291His). Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. This variant is missense, NM_001127510.3:c.6873A>T, p.(Gln2291His), so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 applies only to synonymous or qualifying intronic variants; this missense variant is out of scope.
Evidence considered
  • The APC ClinGen InSiGHT VCEP specification defines BP7 for synonymous or qualifying intronic variants with no predicted splice impact.
  • Variant consequence is missense: NM_001127510.3:c.6873A>T produces p.(Gln2291His).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.147. BayesDel score = -0.36177.

8 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

  • Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.
    Johnston JJ et al. · 2012
    This study analyzed 572 ClinSeq participants across 37 cancer-associated genes and listed APC as associated with familial adenomatous polyposis, but the supplied extraction does not identify APC c.6873A>T or p.(Q2291H) and provides no exact-variant phenotype or enrichment result.
    Does not name this variant
    PMID 22703879 ↗
    Quoted passage
    APC NG_008481.4 familial adenomatous polyposis 175100, 611731, and 135290 45

    Table 1, The 37 Cancer-Associated Genes Analyzed in this Study

  • Guidelines for biomarker testing in colorectal carcinoma (CRC): a national conse
    This consensus guideline discusses genetic testing for hereditary colorectal cancer and mentions APC only at gene level; it provides no exact-variant phenotype, prevalence, case-control, or alternate-basis evidence.
    Does not name this variant
    PMID 22855150 ↗
    Quoted passage
    Other biomarkers, such as genes involved in the deoxyribonucleic acid (DNA) repair pathway or the APC gene, are already routinely tested to determine the subject's susceptibility to hereditary CRC.

    Introduction

  • Recommendations from the EGAPP Working Group: can testing of tumor tissue for mu
    This evidence review concerns pharmacogenomic testing in metastatic colorectal cancer and does not mention APC c.6873A>T or p.(Q2291H), so it supplies no evidence for the requested criteria.
    Does not name this variant
    PMID 23429431 ↗
    Quoted passage
    This statement summarizes the supporting scientific evidence used by the EWG to make recommendations regarding the use of selected pharmacogenomic tests (for codon 12 and 13 mutations in KRAS, the BRAF V600E mutation, variants in NRAS and in PIK3CA, and loss of PTEN and AKT protein expression) in patients with mCRC who are being considered for treatment with cetuximab or panitumumab.

    Review of Scientific Evidence, page 519

  • ACMG recommendations for reporting of incidental findings in clinical exome and
    This paper does not mention APC c.6873A>T or p.(Q2291H) and provides no exact-variant clinical, phenotype, prevalence, or population evidence.
    Does not name this variant
    PMID 23788249 ↗
  • A systematic approach to assessing the clinical significance of genetic variants
    This paper presents a general framework for variant assessment but does not explicitly mention APC c.6873A>T or p.(Q2291H) and reports no exact-variant findings relevant to this group.
    Does not name this variant
    PMID 24033266 ↗
    Quoted passage
    Our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination.

    Abstract

  • ACMG technical standards and guidelines for genetic testing for inherited colore
    This guideline describes familial adenomatous polyposis at gene and disease level but does not mention APC c.6873A>T or p.(Q2291H) and provides no exact-variant evidence.
    Does not name this variant
    PMID 24310308 ↗
    Quoted passage
    Familial adenomatous polyposis (FAP) is manifested as extensive colonic polyposis caused by mutations in the APC gene and inherited in an autosomal dominant manner.

    Introduction, page 101

  • ACMG policy statement: updated recommendations regarding analysis and reporting
    This ACMG policy statement discusses secondary findings and does not mention APC c.6873A>T or p.(Q2291H), providing no exact-variant evidence for this group.
    Does not name this variant
    PMID 25356965 ↗
    Quoted passage
    When clinical genome-scale (e.g., whole-exome sequencing, whole-genome sequencing) sequencing is performed, written informed consent should be obtained by a qualified genetics health-care professional describing the nature of the test and addressing points such as interpretive uncertainty, privacy, possible impact on other family members, and the inevitable generation of data not immediately relevant to the clinical indication for sequencing.

    Recommendations section, page 1

  • Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.
    Grant RC et al. · 2015
    This study reported no APC mutation carriers among 290 pancreatic-cancer probands and did not explicitly mention APC c.6873A>T or p.(Q2291H), so it provides no exact-variant phenotype or prevalence evidence.
    Does not name this variant
    PMID 25479140 ↗
    Quoted passage
    The lack of mutations in APC, PRSS1, and STK11 does not eliminate the possibility that these genes cause a small proportion of PC.

    Discussion, paragraph 4

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

gnomAD v4.1 374 / 1,613,966 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 14 Likely benign · 4 Uncertain significance · 1 Benign · 1 Likely Benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000231727; MAF= 0.02317%, 374/1613966 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000300869; MAF= 0.03009%, 355/1179916 alleles, homozygotes = 0); grpmax FAF= 0.00027477.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000145204; MAF= 0.01452%, 41/282362 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000294972; MAF= 0.02950%, 38/128826 alleles, homozygotes = 0); grpmax FAF= 0.00022755.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (14 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 41534)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.147. BayesDel score = -0.36177.

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; COSV105854020, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.