0%
APCc.2805C>TLikely benign
Print report
Variant interpretation report

APC c.2805C>T, p.(Tyr935=)

NM_001127510.3:c.2805C>T NP_001120982.1:p.(Tyr935=) Synonymous · exon 17 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About APC

APC is a tumor suppressor gene whose protein acts as a key brake on the Wnt signaling pathway by helping mark the growth-promoting protein beta-catenin for destruction; it also participates in cell migration, adhesion, and apoptosis. Inherited mutations in APC cause familial adenomatous polyposis (FAP), an autosomal dominant condition characterized by numerous colorectal polyps and a very high risk of colorectal cancer, with related forms including attenuated FAP and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Somatic APC mutations are found in roughly 50-80% of sporadic colorectal cancers, where they act as early tumor-initiating events, and are also observed in some breast, stomach, and prostate cancers. Loss of APC function leaves Wnt signaling abnormally active, driving uncontrolled cell growth, which makes APC a central tumor suppressor in colorectal cancer.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen APC VCEP v2.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BS1Strong
BS1 · strong

Met at Strong: gnomAD v2.1 non-cancer Popmax allele frequency 0.000686 (0.069%) exceeds the 0.001% BS1 threshold.

BP4Supporting
BP4 · supporting

Met at Supporting: two in silico predictors found no splicing impact (SpliceAI max delta 0.00) for this synonymous variant.

BP7Supporting
BP7 · supporting

Met at Supporting: SpliceAI and Pangolin predict no splice-site impact, consistent with a benign synonymous variant.

Recorded classification: Likely benign

Likely Benign: BS1 strong (gnomAD non-cancer Popmax AF 0.0686% exceeds the >=0.001% threshold), reinforced by BP4 and BP7; no pathogenic criterion is met.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
818 / 1,614,184 alleles

gnomAD v4.1: 818 / 1,614,184 alleles. Recorded AF 0.000506758. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000457252; MAF= 0.04573%, 129/282120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000777049; MAF= 0.07770%, 100/128692 alleles, homozygotes = 0); grpmax FAF= 0.00068567.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0011399413744436, 21/18422 alleles, homozygotes = 0).

Applied · BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
21 reported laboratory submissions

13 Likely benign · 8 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

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

This variant has previously been reported in somatic cancers (COSMIC; COSV104567570, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 3 met · 4 not met · 9 not assessed · 12 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

Variant NM_001127510.3:c.2805C>T is a synonymous single-nucleotide substitution: NP_001120982.1:p.(Tyr935=), identical in canonical NM_000038.6 (ClinVar title NM_000038.6(APC):c.2805C>T (p.Tyr935=)); consequence class is synonymous with no premature stop, frameshift, splice-site, initiation-codon, or whole-exon deletion effect.

The variant sits deep within the APC terminal giant exon (exon 17 of NM_001127510.3; exon 15 in canonical NM_000038.6 numbering per PMID:12173026), ~846 nt from the exon start and remote from all splice junctions; SpliceAI predicts no splice impact (max delta score 0.00).

No loss-of-function or protein-length consequence is produced, so all three consequence-based criteria in this group are not applicable: PVS1 (not a null variant; not in the APC VCEP PVS1 decision-tree lists), PM4 (Not Applicable per APC VCEP v2.1; no in-frame indel/stop-loss), and BP3 (Not Applicable per APC VCEP v2.1; not an in-frame indel).

The InSiGHT APC VCEP v2.1 specification governs; generic ACMG/AMP (PMID:25741868) definitions were consulted only as a cross-check and would not alter any of the three determinations.

Met · 3

BS1 StrongMet at Strong: gnomAD v2.1 non-cancer Popmax allele frequency 0.000686 (0.069%) exceeds the 0.001% BS1 threshold. Details ▾Hide ▴
Reasoning

BS1 is met at Strong under the APC VCEP rule. The prescribed gnomAD v2.1 non-cancer Popmax Filtering AF is 0.00068567 (0.068567%), which is well above the BS1 threshold of 0.001% (0.00001). The result is based on the specified Popmax metric rather than the overall allele frequency.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.001% (0.00001).
Evidence considered
  • The APC VCEP specifies BS1 at Strong when gnomAD Popmax Filtering AF is >= 0.001% (0.00001), using the non-cancer gnomAD v2.1 dataset.
  • gnomAD v2.1 reports Popmax Filtering AF 0.00068567 (0.068567%), exceeding 0.00001; its highest observed population AF is 0.000777049 in European (non-Finnish) individuals, with 100/128692 alleles and no homozygotes.
  • The variant is also observed in gnomAD v4.1 at Popmax Filtering AF 0.00057528, providing concordant population-frequency evidence, although the APC VCEP specifically directs use of gnomAD v2.1.
Sources
cspec ↗gnomad_v2 ↗
BP4 SupportingMet at Supporting: two in silico predictors found no splicing impact (SpliceAI max delta 0.00) for this synonymous variant. Details ▾Hide ▴
Reasoning

This synonymous APC variant has concordant no-impact splice predictions from two predictors available in the SpliceAI lookup. APC VCEP permits BP4_Supporting for synonymous variants when multiple in silico splicing predictors suggest no impact on the gene or gene product.

Rule
APC VCEP BP4 (Supporting): synonymous or intronic variants with multiple in silico splicing predictors suggesting no impact on the gene or gene product.
Evidence considered
  • APC VCEP BP4 is applicable to synonymous or intronic variants when multiple in silico splicing predictors suggest no impact on the gene or gene product; BP4 is not applicable to missense variants.
  • SpliceAI reported DS_AG, DS_AL, DS_DG, and DS_DL all 0.00 (maximum delta 0.00), and Pangolin splice gain/loss values were 0.001 and -0.001, respectively; both predictors indicate no material splice effect for NM_001127510.3:c.2805C>T.
Sources
cspec ↗spliceai ↗
BP7 SupportingMet at Supporting: SpliceAI and Pangolin predict no splice-site impact, consistent with a benign synonymous variant. Details ▾Hide ▴
Reasoning

APC c.2805C>T is a synonymous variant. The available SpliceAI and Pangolin predictions show no impact on splice consensus use or creation of a new splice site. APC VCEP explicitly allows use of BP7 together with BP4, so this is not double-counted as an alternative to BP4.

Rule
APC VCEP BP7 (Supporting): synonymous or intronic variants at or beyond +7/-21 with multiple splicing prediction algorithms predicting no splice-consensus impact or new splice site; BP7 may be used with BP4.
Evidence considered
  • APC VCEP BP7 applies at Supporting strength to a synonymous or intronic variant at or beyond +7/-21 when multiple splicing prediction algorithms predict no impact on the splice consensus sequence and no new splice site; the APC VCEP instructions explicitly state that BP7 may be used with BP4.
  • SpliceAI reported all four delta scores as 0.00 (maximum delta 0.00), with no predicted splice gain or loss. Pangolin splice gain/loss values were 0.001 and -0.001, respectively, also indicating no meaningful predicted splice alteration.
Sources
cspec ↗spliceai ↗

Not met · 4 · evaluated, threshold not reached

PM2 Not met: gnomAD allele frequency 0.000457 (allele count 129) far exceeds the PM2 supporting threshold of <=0.000003. Details ▾Hide ▴
Reasoning

PM2 is not met under the APC VCEP threshold. PM2 Supporting requires AF <=0.000003 when allele count is >1, or AF <0.00001 when allele count is <=1. This variant has allele count 129 and AF 0.000457252 in gnomAD v2.1, including Popmax Filtering AF 0.00068567; gnomAD v4.1 reports allele count 818 and AF 0.000506758. These frequencies are substantially above the VCEP PM2 threshold, so the variant is not rare enough for PM2.

Rule
Rare in controls, defined by an allele frequency <= 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is <= 1.
Evidence considered
  • The APC VCEP defines PM2 Supporting as AF <=0.000003 when allele count is >1, or AF <0.00001 when allele count is <=1.
  • gnomAD v2.1 reports total allele count 129/282120 and AF 0.000457252, with Popmax Filtering AF 0.00068567; the allele count is >1 and the AF greatly exceeds 0.000003.
  • gnomAD v4.1 reports allele count 818/1614184 and AF 0.000506758, also greatly exceeding 0.000003.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 Not met: this synonymous variant shows no predicted splice impact, whereas PP3 requires multiple in silico predictors supporting a deleterious splicing effect. Details ▾Hide ▴
Reasoning

APC c.2805C>T is synonymous (p.Tyr935=). The APC VCEP permits PP3 for non-canonical splice variants only when multiple in silico splicing predictors support a deleterious effect. The available predictions instead show no splice impact, so PP3 is not met.

Rule
APC VCEP PP3 (Supporting): non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • APC VCEP PP3 specifies Supporting strength for non-canonical splice variants only when multiple in silico splicing predictors support a deleterious effect; it does not permit amino-acid conservation/evolution prediction models for presumed missense variants.
  • SpliceAI reported DS_AG, DS_AL, DS_DG, and DS_DL all 0.00 (maximum delta 0.00); the same lookup reported Pangolin splice gain/loss values of 0.001 and -0.001, respectively. These results do not support a deleterious splice effect.
Sources
cspec ↗spliceai ↗
BA1 Not met: gnomAD non-cancer Popmax allele frequency 0.000686 (0.069%) is below the 0.1% BA1 threshold. Details ▾Hide ▴
Reasoning

BA1 is not met under the APC VCEP rule because the prescribed gnomAD non-cancer Popmax Filtering AF is below 0.1% (0.001): 0.00068567 in gnomAD v2.1 and 0.00057528 in gnomAD v4.1. The gnomAD-Canada overall AF is 0.00113994, above 0.1%, but it is not the VCEP-prescribed gnomAD v2.1 non-cancer Popmax metric and is therefore not used to trigger BA1. No threshold-based BA1 evidence is present in the specified dataset/metric.

Rule
GnomAD Popmax Filtering Allele Frequency (AF) >= 0.1% (0.001).
Evidence considered
  • The APC VCEP specifies BA1 as gnomAD Popmax Filtering AF >= 0.1% (0.001), with the general recommendation to use the non-cancer gnomAD v2.1 dataset.
  • gnomAD v2.1 reports Popmax Filtering AF 0.00068567 (0.068567%), below 0.001.
  • gnomAD v4.1 reports Popmax Filtering AF 0.00057528 (0.057528%), below 0.001.
  • gnomAD-Canada reports overall AF 0.0011399413744436 (0.113994%), but this is not the VCEP-specified gnomAD v2.1 Popmax metric; treating it as a BA1 trigger would be a dataset/metric threshold artifact.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 Not met: gnomAD reports zero homozygotes, and no healthy individuals with the required phenotype details were documented. Details ▾Hide ▴
Reasoning

BS2 is not met. The APC VCEP requires either at least 3 healthy-individual points for Supporting or at least 10 points for Strong, or at least 2 observations in the homozygous state for Strong. The available gnomAD v2.1 and v4.1 data report zero homozygotes, and no individually documented healthy participants with the required age, colonoscopy, indication, or phenotype details are available. The VCEP also states that gnomAD heterozygous individuals cannot be used as healthy individuals because phenotype information is limited.

Rule
>= 10 points for healthy individuals OR >= 2 times in homozygous state for Strong; >= 3 points for healthy individuals for Supporting. A qualifying 1-point healthy individual requires age >=50 years plus fewer than 5 adenomatous polyps and absence of specified features, or age >=50 years with colorectal cancer/polyposis not being the testing indication; a 0.5-point individual is defined by control/non-cancer/normal/unaffected keywords.
Evidence considered
  • The APC VCEP defines BS2 Supporting as >=3 healthy-individual points and BS2 Strong as >=10 healthy-individual points or >=2 homozygous observations.
  • The APC VCEP prohibits using the gnomAD v2.1 non-cancer dataset for heterozygous healthy individuals because phenotype information is limited, but permits it for searching for homozygous individuals.
  • gnomAD v2.1 reports total homozygotes = 0, and gnomAD v4.1 reports total homozygotes = 0; no homozygous BS2 evidence is present.
Still missing
  • No qualifying individually documented healthy individuals with APC-specific phenotype and age information.
  • No homozygous observations in the available gnomAD v2.1 or v4.1 data.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 9 · no assessment recorded

PS2 Not assessed: no case evidence shows this variant arose de novo; parental genotypes and maternity/paternity confirmation are absent. Details ▾Hide ▴
Reasoning

No case-level evidence documents that NM_001127510.3:c.2805C>T was de novo in an affected proband. The available variant report lists the synonymous variant as TAC>TAT (p.(Y935=)) in exon 15 but provides no proband-level parental genotypes, maternity and paternity confirmation, or phenotype-linked de novo observation. Under the APC InSiGHT specification, PS2 requires de novo scoring based on phenotype points and confirmed or unconfirmed parental relationships; those inputs are absent.

Rule
APC InSiGHT V2.1 PS2: de novo scoring requires phenotype points; confirmed parental relationships yield 2 points for a phenotype score of at least 1 or 1 point for a phenotype score of 0.5, while unconfirmed relationships yield 1 or 0.5 points respectively. PS2 strength thresholds are Very Strong at >=4 scores, Strong at 2-3.5, and Moderate at 1-1.5.
Evidence considered
  • The APC InSiGHT VCEP specification applies PS2 using de novo scores: at least 4 scores for Very Strong, 2-3.5 for Strong, and 1-1.5 for Moderate; the score depends on phenotype points and whether parental relationships are confirmed.
  • PMID:12173026 reports the exact synonymous variant as TAC>TAT, Y935Y, polymorphism in Table 2 from APC EMD screening of 75 Belgian patients with FAP or AFAP, but does not report parental testing or a de novo determination for this variant.
Still missing
  • Affected proband phenotype and phenotype-point assessment
  • Parental testing results for both biological parents
  • Confirmation of maternity and paternity
  • Evidence excluding mosaicism or other non-de novo explanations
Sources
cspec ↗PMID:12173026 ↗
PS3 Not assessed: no RNA or protein functional assay results were available to test for a pathogenic transcript or protein effect. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP specification requires RNA evidence of a pathogenic transcript consequence (premature stop codon or specified exon skipping/loss, with strength calibrated by full-length transcript abundance) or, for variants in the beta-catenin binding domain, a protein assay showing increased beta-catenin-regulated transcription and/or decreased beta-catenin binding. The exact variant NM_001127510.3:c.2805C>T (p.(Y935=)) is reported in an APC cohort as a polymorphism, but the available source does not report an RNA or protein functional assay, assay controls, transcript abundance, or beta-catenin assay result. PS3 therefore cannot be applied.

Rule
APC VCEP PS3: RNA assays must show a premature stop codon or in-frame skipping of exon 13 or 14 with absent or <10% full-length transcript for Very Strong/Strong, or other specified transcript abnormalities for Moderate/Supporting; protein assays may support PS3 when they show increased beta-catenin-regulated transcription and/or decreased beta-catenin binding for variants within APC codons 959-2129.
Evidence considered
  • The APC InSiGHT VCEP PS3 specification calibrates PS3 Very Strong, Strong, Moderate, and Supporting using RNA findings and full-length transcript abundance; its protein-assay pathway is limited to increased beta-catenin-regulated transcription and/or decreased beta-catenin binding for variants in codons 959-2129.
  • The paper-extract entry for PMID:12173026 reports the exact variant as TAC>TAT at codon Y935 in exon 15 and labels it a polymorphism, but describes EMD screening rather than a functional RNA or protein assay and provides no transcript, protein-activity, control, or quantitative assay result.
  • No other already-extracted paper in the case bundle provides variant-specific functional assay evidence for c.2805C>T.
Still missing
  • No validated RNA assay result for c.2805C>T is available, including transcript structure and full-length transcript percentage.
  • No validated protein functional assay result is available; additionally, p.Tyr935 is outside the APC beta-catenin binding domain specified by the VCEP (codons 959-2129).
  • No assay-control, biological-relevance, or replication details are available for this variant.
Sources
cspec ↗PMID:12173026 ↗
PS4 Not assessed: no proband counts, phenotype-point data, or case-control enrichment analysis were available for this variant. Details ▾Hide ▴
Reasoning

The APC-specific framework requires phenotype-point totals for PS4. The available exact-variant paper identifies c.2805C>T as a polymorphism in an APC FAP/AFAP screening cohort but does not provide an attributable proband count, phenotype-point data, or case-control enrichment analysis; therefore no PS4 strength can be assigned.

Rule
APC VCEP PS4: phenotype-point thresholds are Supporting 1-1.5, Moderate 2-3.5, Strong 4-15.5, and Very Strong at least 16 points.
Evidence considered
  • APC VCEP PS4 strengths require 1-1.5, 2-3.5, 4-15.5, or at least 16 phenotype points for Supporting, Moderate, Strong, or Very Strong evidence, respectively.
  • APC VCEP Table 1 defines phenotype points per proband; no such pointable phenotype information is available for this variant in the supplied evidence.
  • PMID:12173026 lists the exact change in an APC FAP/AFAP screening cohort as a polymorphism, but the extracted table entry does not state the number of carriers or their phenotype details.
Still missing
  • Exact-variant phenotype-point total using the APC VCEP Table 1 definitions.
  • Case and control counts, or an equivalent appropriately ascertained enrichment analysis, for c.2805C>T.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2vcep_table_1_262PMID:12173026 ↗
PM6 Not assessed: no case evidence supports an assumed de novo occurrence; inheritance and parental testing are undocumented. Details ▾Hide ▴
Reasoning

No case-level evidence supports an assumed de novo occurrence of NM_001127510.3:c.2805C>T. The available exact-variant publication provides a cohort table entry and does not identify the variant in a proband with parental testing or describe its inheritance. Therefore no APC de novo score can be assigned for PM6.

Rule
APC InSiGHT V2.1 PM6: assumed de novo without confirmed paternity and maternity; Supporting requires 0.5 de novo score, Moderate 1-1.5, and Strong 2-3.5. De novo scores are curated using the APC phenotype-point and parental-relationship tables.
Evidence considered
  • The APC InSiGHT VCEP specification assigns PM6 from de novo scores: Supporting at 0.5, Moderate at 1-1.5, and Strong at 2-3.5.
  • PMID:12173026 lists the exact variant as a polymorphism in Table 2 but contains no inheritance or parental-testing data from which an assumed-de-novo score could be calculated.
Still missing
  • Affected proband phenotype and phenotype-point assessment
  • Parental genotype results or a documented assumed-de-novo pedigree
  • Information on whether maternity and paternity were confirmed
Sources
cspec ↗PMID:12173026 ↗
PP1 Not assessed: no family segregation data exist for this variant; no affected relatives or informative meioses were documented. Details ▾Hide ▴
Reasoning

No segregation family is described for the exact variant. The available report identifies NM_001127510.3:c.2805C>T (p.(Y935=)) in a screening cohort and labels it a polymorphism, but does not provide affected relatives, variant-positive relatives, phenotype-positive obligate carriers, or countable meioses. The APC VCEP PP1 thresholds therefore cannot be met or scored.

Rule
APC InSiGHT V2.1 PP1: variant segregates in 3-4 meioses in at least 1 family for Supporting, 5-6 meioses in at least 1 family for Moderate, or at least 7 meioses in at least 2 families for Strong; affected individuals must satisfy the APC phenotype-point requirement.
Evidence considered
  • The APC InSiGHT VCEP requires affected individuals to have at least 0.5 phenotype point and counts only genotype- and phenotype-positive individuals or phenotype-positive obligate carriers. PP1 is Supporting for 3-4 segregating meioses, Moderate for 5-6 meioses in at least one family, and Strong for at least 7 meioses in at least 2 families.
  • PMID:12173026 contains the exact variant in Table 2 but reports no family segregation, relative genotypes, phenotype-linked carriers, or meioses for this variant.
Still missing
  • Family pedigrees and affected-relative phenotypes
  • Genotypes of affected and unaffected relatives
  • Number of informative segregating meioses
  • Independent families, if any
Sources
cspec ↗PMID:12173026 ↗
BS3 Not assessed: no RNA or protein functional assay in a patient sample was available to demonstrate normal function. Details ▾Hide ▴
Reasoning

The applicable APC InSiGHT VCEP specification requires a normal RNA assay in a constitutional patient sample, with biallelic expression and/or nonsense-mediated decay inhibition for BS3 Strong, or without those additional controls for BS3 Supporting. It also permits BS3 Supporting for a protein assay showing retention of beta-catenin-regulated transcription activity comparable to wild type, but only for variants within the beta-catenin binding domain. The available exact-variant report provides no RNA or protein functional assay and no assay controls. BS3 therefore cannot be applied.

Rule
APC VCEP BS3: Strong requires a constitutional-sample RNA assay showing no mRNA aberration plus biallelic expression and/or nonsense-mediated decay inhibition; Supporting allows the same normal RNA result without those additional demonstrations, or a protein assay showing wild-type-comparable beta-catenin-regulated transcription activity for variants within APC codons 959-2129.
Evidence considered
  • The APC InSiGHT VCEP BS3 specification requires a normal constitutional-sample RNA assay; BS3 Strong additionally requires demonstration of biallelic expression and/or use of nonsense-mediated decay inhibition, while BS3 Supporting can be used without those controls. Its protein-assay option is restricted to the APC beta-catenin binding domain and requires retention of transcriptional activity comparable to wild type.
  • The paper-extract entry for PMID:12173026 reports the exact c.2805C>T (p.(Y935=)) observation from EMD screening but does not report a normal RNA assay, protein assay, biallelic expression, nonsense-mediated decay inhibition, or assay controls.
  • No other already-extracted paper in the case bundle provides variant-specific benign functional assay evidence for c.2805C>T.
Still missing
  • No constitutional-sample RNA assay demonstrating no mRNA aberration is available for c.2805C>T.
  • No evidence of biallelic expression or nonsense-mediated decay inhibition is available.
  • No protein assay demonstrating retention of beta-catenin-regulated transcription activity comparable to wild type is available; p.Tyr935 is outside the VCEP beta-catenin binding domain (codons 959-2129).
Sources
cspec ↗PMID:12173026 ↗
BS4 Not assessed: no affected family member without this variant was documented, so lack of segregation cannot be shown. Details ▾Hide ▴
Reasoning

No affected family member without NM_001127510.3:c.2805C>T is documented. The available exact-variant publication does not provide an informative pedigree, affected non-carrier genotype, or phenotype-point data. Consequently, the APC VCEP BS4 threshold for lack of segregation cannot be evaluated.

Rule
APC InSiGHT V2.1 BS4: Supporting requires an affected member without the variant with at least 0.5 phenotype point; Strong requires one such member with at least 1 point or at least two such members each with at least 0.5 point.
Evidence considered
  • The APC InSiGHT VCEP defines BS4 as an affected member without the variant scoring at least 0.5 phenotype point for Supporting, or one affected non-carrier scoring at least 1 point or two affected non-carriers each scoring at least 0.5 point for Strong; phenocopies and multiple pathogenic variants can confound lack of segregation.
  • PMID:12173026 reports the exact variant in a cohort table but does not report affected non-carriers, family-level phenotypes, or a pedigree suitable for BS4 evaluation.
Still missing
  • Affected relatives tested negative for the variant
  • Phenotype severity and phenotype points for any affected non-carrier
  • Assessment for phenocopies or more than one pathogenic cause in the family
Sources
cspec ↗PMID:12173026 ↗
BP2 Not assessed: no second pathogenic APC variant in trans, or repeated unknown-phase observations, was documented. Details ▾Hide ▴
Reasoning

The APC/InSiGHT VCEP permits BP2 at Supporting strength when the variant is observed in trans with a (Likely) Pathogenic APC variant, or at least three times with different (Likely) Pathogenic APC variants in unknown phase. The available report lists APC c.2805C>T (p.(Y935=)) as a polymorphism in an FAP/AFAP screening cohort, but does not document a second pathogenic APC variant, phase, cis/trans relationship, or three qualifying unknown-phase observations. Therefore BP2 cannot be established or excluded from the available evidence.

Rule
Supporting: observed in trans with a (Likely) Pathogenic APC variant OR observed at least 3 times in unknown phase with different (Likely) Pathogenic APC variants.
Evidence considered
  • The APC/InSiGHT VCEP rule requires observation in trans with a (Likely) Pathogenic APC variant, or at least three observations with different (Likely) Pathogenic APC variants in unknown phase, for BP2 Supporting.
  • PMID:12173026 reports the exact synonymous variant as TAC>TAT, p.(Y935=), in exon 15 and labels it a polymorphism among Belgian patients screened for FAP or AFAP; the extracted report does not provide co-occurring APC pathogenic variants or phase information.
Still missing
  • Variant-level co-occurrence data with a known (Likely) Pathogenic APC variant are not available.
  • Parental or offspring testing and other phase information are not available.
  • At least three qualifying observations with different (Likely) Pathogenic APC variants in unknown phase are not documented.
Sources
cspec ↗PMID:12173026 ↗
BP5 Not assessed: no evidence documents an alternate genetic basis explaining the polyposis phenotype. Details ▾Hide ▴
Reasoning

For APC, BP5 is only applicable when an alternate genetic basis explains the colorectal polyposis phenotype. The supplied evidence contains no patient-level phenotype or testing result documenting such an alternate molecular diagnosis.

Rule
APC VCEP BP5: applicable only for an alternate genetic basis of the colorectal polyposis phenotype.
Evidence considered
  • The APC VCEP restricts BP5 to an alternate genetic basis of the colorectal polyposis phenotype.
  • No alternate molecular diagnosis or patient phenotype is provided in the consolidated evidence bundle.
Still missing
  • Patient-level colorectal polyposis phenotype and comprehensive testing results establishing an alternate genetic cause.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2805C>T is a synonymous substitution (p.Tyr935=), not a null variant, with no predicted splicing effect (SpliceAI max delta 0.00). Details ▾Hide ▴
Reasoning

PVS1 requires a null variant (nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or whole-exon deletion) in a gene where LOF is the established mechanism. NM_001127510.3:c.2805C>T is a synonymous substitution (NP_001120982.1:p.(Tyr935=); identical change in canonical NM_000038.6(APC):c.2805C>T p.Tyr935= per ClinVar) located ~846 nt into the terminal giant exon (exon 17 of NM_001127510.3; exon 15 of NM_000038.6), remote from any splice junction. The governing InSiGHT APC VCEP v2.1 (cspec) restricts PVS1 to null variants evaluated through its modified decision tree (Figure 1, lists A-E of specific splice variants); c.2805C>T appears in none of these lists and is not a splice-consensus change. SpliceAI predicts no splicing effect (max delta score 0.00), so no splicing-mediated LOF route is predicted. The change introduces no premature stop, no frameshift, no alteration of the initiation codon, and no exon deletion; therefore PVS1 cannot be applied at any strength.

Evidence considered
  • Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP specification for APC v2.1 (cspec), which states PVS1 applies to null variants 'as per modified decision tree (Figure 1)'; that decision tree enumerates specific nonsense/frameshift and splice-site variants in lists A-E and does not include c.2805C>T or any deep-exonic synonymous position.
  • Variant consequence is synonymous: Mutalyzer/VariantValidator normalization gives NM_001127510.3(NP_001120982.1):p.(Y935=), and ClinVar titles the record NM_000038.6(APC):c.2805C>T (p.Tyr935=), confirming no amino-acid change in either transcript (both share the CCDS4107 CDS).
  • The variant is positioned in the terminal giant exon (VariantValidator: exon 17 of NM_001127510.3; exon boundaries place c.2805 ~846 nt downstream of the exon 17 acceptor at c.1959), i.e., remote from any intron boundary, so no canonical or cryptic splice-consensus disruption is plausible.
  • SpliceAI lookup (spliceai source) reports all delta scores 0.00 (DS_AG/DS_AL/DS_DG/DS_DL = 0.0; max_delta_score 0.0), i.e., no predicted splice impact.
  • Generic ACMG/AMP PVS1 (PMID:25741868) likewise applies only to null variants (nonsense/frameshift/canonical splice/initiation/exon loss); it would not be triggered even if the VCEP specification were unavailable, though the VCEP governs here.
  • PMID:12173026 lists the variant as TAC>TAT at codon Y935 (Y935Y) in exon 15, classified as a polymorphism, confirming a protein-neutral synonymous change with no truncating or length-altering consequence.
  • pvs1_gene_context.json confirms APC germline LOF is an established mechanism (gene gate 'eligible'), so the reason PVS1 is not applied is exclusively the non-null nature of this variant, not the gene-level mechanism.
Still missing
  • No RNA-based assay for this variant is available in the evidence bundle; however, PVS1 applicability does not hinge on it because the variant is a deep-exonic synonymous change, not a null variant under the APC VCEP decision tree. A possible splicing effect of a synonymous variant would be addressed by other criteria (e.g., BP7/BS3), not PVS1.
Sources
cspec ↗PMID:25741868 ↗PMID:12173026 ↗PMID:24033266 ↗
PS1 N/ANot applicable: PS1 requires a missense change or splicing effect at the same nucleotide; this synonymous polymorphism (p.Tyr935=) is neither. Details ▾Hide ▴
Reasoning

The APC VCEP specification limits missense PS1 to a variant producing the same amino-acid change as an established pathogenic or likely pathogenic missense variant; its splice branch requires a splicing effect at the same nucleotide. NM_001127510.3:c.2805C>T is synonymous, NP_001120982.1:p.(Tyr935=), and the available exact-variant report identifies it as TAC>TAT, Y935Y, a polymorphism. No evidence establishes that this synonymous substitution causes splicing at the nucleotide. Therefore PS1 is not applicable.

Rule
For APC, PS1 missense requires the same amino-acid change as an established pathogenic or likely pathogenic missense variant; the splice branch requires a demonstrated/supported splicing effect at the same nucleotide.
Evidence considered
  • The APC VCEP PS1 rule requires the assessed missense variant to result in the same amino-acid change as an established pathogenic/likely pathogenic missense variant, or requires an established same-nucleotide splicing effect for splice variants.
  • The case normalization is NP_001120982.1:p.(Tyr935=), so this is a synonymous rather than missense change.
  • PMID:12173026 lists the exact change as TAC>TAT at codon Y935 in exon 15 and classifies it as a polymorphism; the source does not establish a splice effect.
Sources
cspec ↗PMID:12173026 ↗
PM1 VCEPNot applicable: the APC expert panel does not use PM1, and this synonymous change is not a missense variant in a functional hotspot. Details ▾Hide ▴
Reasoning

The applicable APC VCEP specification explicitly designates PM1 as not applicable. In addition, the assessed variant is synonymous (p.(Tyr935=)), not a missense change for which a critical functional domain or mutational hotspot would be used under this criterion. The case-specific vcep_materials.json domain_tables object is empty, so there is no authoritative domain-table entry to apply.

VCEP rule
The APC VCEP specification designates PM1 as not applicable.
Evidence considered
  • The governing ClinGen InSiGHT APC specification marks PM1 as Not Applicable.
  • The case variant normalizes to NP_001120982.1:p.(Tyr935=), a synonymous change rather than a missense residue substitution.
  • The case-specific vcep_materials.json domain_tables key is present but contains no APC entry.
Sources
cspec ↗
PM3 VCEPNot applicable: the APC expert panel does not use PM3; APC-associated polyposis follows autosomal dominant inheritance. Details ▾Hide ▴
Reasoning

The APC/InSiGHT VCEP specification explicitly designates PM3 as not applicable for APC. The applicable inheritance model is autosomal dominant APC-associated polyposis, and no recessive allelic evidence is required for this criterion.

VCEP rule
Not Applicable per the APC/InSiGHT VCEP specification.
Evidence considered
  • The APC/InSiGHT VCEP framework lists PM3 as Not Applicable.
  • The case bundle provides no phase or biallelic disease evidence that would override the gene-specific PM3 applicability designation.
Sources
cspec ↗
PM4 VCEPNot applicable: the APC expert panel does not use PM4, and this synonymous change leaves protein length unaltered. Details ▾Hide ▴
Reasoning

PM4 (protein length change due to in-frame deletion/insertion or stop-loss variant) is marked Not Applicable in the governing InSiGHT APC VCEP v2.1 specification (supplementary material: PM4 'Not used due to limited available data'). Independently of applicability, the variant cannot satisfy PM4: c.2805C>T is a single-nucleotide synonymous substitution (p.Tyr935=) that neither deletes nor inserts coding sequence and does not alter protein length in any frame.

Evidence considered
  • cspec marks PM4 as Not Applicable for APC (case_summary cspec criteria: PM4 applicability 'Not Applicable'); the APC VCEP supplementary material states 'PM4 Protein length changes due to in-frame deletions/insertions: Not used due to limited available data.'
  • Variant is synonymous (p.Tyr935= per Mutalyzer/VariantValidator normalization and ClinVar record NM_000038.6(APC):c.2805C>T (p.Tyr935=)); no coding sequence is removed or inserted and no stop-loss occurs, so no protein length change is produced under any transcript.
  • Generic ACMG/AMP PM4 (PMID:25741868) applies to in-frame indels or stop-loss variants only, which does not describe a synonymous substitution; generic fallback would likewise not be met, but the VCEP specification governs.
Sources
cspec ↗PMID:25741868 ↗PMID:12173026 ↗
PM5 N/ANot applicable: PM5 applies only to missense changes at established pathogenic residues; this variant is synonymous (p.Tyr935=). Details ▾Hide ▴
Reasoning

The APC VCEP PM5 rule applies to a missense change at a residue where another missense variant has been established as pathogenic or likely pathogenic, with the specified Grantham-distance condition. NM_001127510.3:c.2805C>T is synonymous, NP_001120982.1:p.(Tyr935=), and the PM5 candidate artifact found no eligible missense search because the consequence is synonymous. Therefore PM5 is not applicable.

Rule
For APC, PM5 requires an assessed missense variant at a residue with an established pathogenic/likely pathogenic missense comparator and, for the applicable strength, the required Grantham-distance relationship.
Evidence considered
  • The APC VCEP PM5 rule is restricted to different missense variants at a residue represented by an established pathogenic or likely pathogenic APC missense variant, with the required Grantham-distance comparison.
  • The assessed variant is synonymous, p.(Tyr935=), and does not define an altered amino-acid residue.
  • The case PM5 candidate artifact reports zero eligible candidates because the variant consequence class is synonymous, not missense.
Sources
cspec ↗pm5_candidates
PP2 VCEPNot applicable: the APC expert panel does not use PP2; the gene-specific specification takes precedence. Details ▾Hide ▴
Reasoning

The governing APC VCEP specification explicitly designates PP2 as not applicable. No generic PP2 assessment is used because an applicable gene-specific specification exists.

VCEP rule
The APC VCEP specification designates PP2 as not applicable.
Evidence considered
  • The applicable ClinGen InSiGHT APC specification marks PP2 as Not Applicable; the gene-specific rule takes precedence over generic ACMG/AMP guidance.
Sources
cspec ↗
PP4 VCEPNot applicable: the APC expert panel captures phenotype evidence under its PS4 framework rather than PP4. Details ▾Hide ▴
Reasoning

The APC VCEP specification designates PP4 not applicable because phenotype evidence is captured under its PS4 phenotype-point framework.

VCEP rule
APC VCEP: PP4 not applicable; phenotype specificity is assessed through PS4 phenotype points.
Evidence considered
  • The APC VCEP supplementary specification states that PP4 is already captured by the APC-specific PS4 specifications.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2
PP5 VCEPNot applicable: not used by the APC expert panel, and ClinVar has no expert-panel pathogenic assertion for this variant. Details ▾Hide ▴
Reasoning

PP5 is not applicable under the APC VCEP specification. Independently, ClinVar contains no exact-variant expert-panel Pathogenic or Likely pathogenic assertion; available assertions are ordinary laboratory Benign/Likely benign submissions and cannot trigger PP5.

VCEP rule
APC VCEP: PP5 not applicable.
Evidence considered
  • The APC VCEP specification does not use PP5.
  • The ClinVar exact-variant submission audit reports zero expert-panel submissions; ordinary laboratory assertions must not be used for PP5.
Sources
cspec ↗vcep_apc_specifications_supplementary_material_v2clinvar ↗
BP1 N/ANot applicable: BP1 addresses missense variants; this is a synonymous substitution (p.Tyr935=). Details ▾Hide ▴
Reasoning

The APC VCEP BP1 rule addresses APC missense variants and excludes missense variants in codons 1021-1035, the first 15-amino-acid repeat of the beta-catenin binding domain. The assessed variant is synonymous, p.(Tyr935=), and is not a missense variant; therefore the missense BP1 rule does not apply.

Rule
BP1 is applicable to APC with the exception of missense variants located in the first 15-amino-acid repeat of the beta-catenin binding domain (codons 1021-1035).
Evidence considered
  • The APC VCEP BP1 rule applies to APC missense variants, except those in codons 1021-1035.
  • The case variant normalizes to p.(Tyr935=), a synonymous change, so it is outside the rule's missense scope.
  • PMID:12173026 lists the exact variant as Y935Y and calls it a polymorphism.
Sources
cspec ↗PMID:12173026 ↗
BP3 VCEPNot applicable: the APC expert panel does not use BP3, and this is a synonymous substitution, not an in-frame indel. Details ▾Hide ▴
Reasoning

BP3 (benign supporting for in-frame indels in a repetitive region without known function) is marked Not Applicable in the governing InSiGHT APC VCEP v2.1 specification. Independently of applicability, the variant class does not fit BP3: c.2805C>T is a synonymous single-nucleotide substitution (p.Tyr935=), not an in-frame insertion/deletion, so repeat-region context of a length-altering change is not engaged. No BP3 consideration applies.

Evidence considered
  • cspec marks BP3 as Not Applicable for APC (case_summary cspec criteria: BP3 applicability 'Not Applicable').
  • Generic ACMG/AMP BP3 (PMID:25741868) is defined for in-frame indels located in a repetitive region without known function; the variant is a synonymous SNV (p.Tyr935=), not an indel, so BP3 is not applicable regardless of any repeat-region context at codon 935.
Sources
cspec ↗PMID:25741868 ↗
BP6 VCEPNot applicable: not used by the APC expert panel, and no expert-panel ClinVar submissions exist for this variant. Details ▾Hide ▴
Reasoning

BP6 is not applicable under the APC VCEP specification. The ClinVar exact-variant audit also reports zero expert-panel submissions; ordinary laboratory Benign/Likely benign assertions cannot trigger BP6.

VCEP rule
APC VCEP: BP6 not applicable.
Evidence considered
  • The APC VCEP specification designates BP6 not applicable.
  • The ClinVar exact-variant submission audit reports zero expert-panel submissions; the observed non-expert Benign/Likely benign assertions are insufficient for BP6.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
APC
Transcript
NM_001127510.3
Coding (HGVS c.)
NM_001127510.3:c.2805C>T
Protein (HGVS p.)
NP_001120982.1:p.(Tyr935=)
GRCh38
chr5:112838399 C>T
GRCh37
chr5:112174096 C>T
Location and type
Exon 17 · synonymous
ClinVar
230742, 136408
COSMIC
COSV104567570

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 v4.1 818 / 1,614,184 alleles AF 0.000507 · 0 homozygotes · FAF 0.000575
gnomAD v2.1 129 / 282,120 alleles AF 0.000457 · 0 homozygotes · FAF 0.000686
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00051 · 818 / 1,614,184 alleles · 0 hom · FAF 0.00058
European (non-Finnish)723 / 1,180,020 0.00061
Admixed American25 / 60,022 0.00042
Middle Eastern2 / 6,062 0.00033
Remaining individuals19 / 62,506 0.0003
South Asian26 / 91,086 0.00029
African/African American13 / 75,066 0.00017
European (Finnish)6 / 64,018 9.4e-05
East Asian3 / 44,884 6.7e-05
Ashkenazi Jewish1 / 29,608 3.4e-05
0 alternate alleles recorded in 1 other group: Amish.

gnomAD v2.1

AF 0.00046 · 129 / 282,120 alleles · 0 hom · FAF 0.00069
European (non-Finnish)100 / 128,692 0.00078
Remaining individuals3 / 7,192 0.00042
South Asian9 / 30,606 0.00029
Admixed American9 / 35,408 0.00025
African/African American6 / 24,842 0.00024
European (Finnish)2 / 25,110 8e-05
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, East Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000506758; MAF= 0.05068%, 818/1614184 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000612701; MAF= 0.06127%, 723/1180020 alleles, homozygotes = 0); grpmax FAF= 0.00057528.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000457252; MAF= 0.04573%, 129/282120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000777049; MAF= 0.07770%, 100/128692 alleles, homozygotes = 0); grpmax FAF= 0.00068567.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0011399413744436, 21/18422 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -255 bp
0.000
SpliceAI acceptor gainat +293 bp
0.000
SpliceAI donor lossat -376 bp
0.000
SpliceAI donor gainat -416 bp
0.000
Pangolin splice lossmagnitude shown
-0.001
Pangolin splice gain
0.001

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMet at Supporting: two in silico predictors found no splicing impact (SpliceAI max delta 0.00) for this synonymous variant. Details ▾Hide ▴
Reasoning

This synonymous APC variant has concordant no-impact splice predictions from two predictors available in the SpliceAI lookup. APC VCEP permits BP4_Supporting for synonymous variants when multiple in silico splicing predictors suggest no impact on the gene or gene product.

Rule
APC VCEP BP4 (Supporting): synonymous or intronic variants with multiple in silico splicing predictors suggesting no impact on the gene or gene product.
Evidence considered
  • APC VCEP BP4 is applicable to synonymous or intronic variants when multiple in silico splicing predictors suggest no impact on the gene or gene product; BP4 is not applicable to missense variants.
  • SpliceAI reported DS_AG, DS_AL, DS_DG, and DS_DL all 0.00 (maximum delta 0.00), and Pangolin splice gain/loss values were 0.001 and -0.001, respectively; both predictors indicate no material splice effect for NM_001127510.3:c.2805C>T.
Sources
cspec ↗spliceai ↗
BP7 SupportingMet at Supporting: SpliceAI and Pangolin predict no splice-site impact, consistent with a benign synonymous variant. Details ▾Hide ▴
Reasoning

APC c.2805C>T is a synonymous variant. The available SpliceAI and Pangolin predictions show no impact on splice consensus use or creation of a new splice site. APC VCEP explicitly allows use of BP7 together with BP4, so this is not double-counted as an alternative to BP4.

Rule
APC VCEP BP7 (Supporting): synonymous or intronic variants at or beyond +7/-21 with multiple splicing prediction algorithms predicting no splice-consensus impact or new splice site; BP7 may be used with BP4.
Evidence considered
  • APC VCEP BP7 applies at Supporting strength to a synonymous or intronic variant at or beyond +7/-21 when multiple splicing prediction algorithms predict no impact on the splice consensus sequence and no new splice site; the APC VCEP instructions explicitly state that BP7 may be used with BP4.
  • SpliceAI reported all four delta scores as 0.00 (maximum delta 0.00), with no predicted splice gain or loss. Pangolin splice gain/loss values were 0.001 and -0.001, respectively, also indicating no meaningful predicted splice alteration.
Sources
cspec ↗spliceai ↗
PP3 Not met: this synonymous variant shows no predicted splice impact, whereas PP3 requires multiple in silico predictors supporting a deleterious splicing effect. Details ▾Hide ▴
Reasoning

APC c.2805C>T is synonymous (p.Tyr935=). The APC VCEP permits PP3 for non-canonical splice variants only when multiple in silico splicing predictors support a deleterious effect. The available predictions instead show no splice impact, so PP3 is not met.

Rule
APC VCEP PP3 (Supporting): non-canonical splicing variants require multiple in silico splicing predictors supporting a deleterious effect.
Evidence considered
  • APC VCEP PP3 specifies Supporting strength for non-canonical splice variants only when multiple in silico splicing predictors support a deleterious effect; it does not permit amino-acid conservation/evolution prediction models for presumed missense variants.
  • SpliceAI reported DS_AG, DS_AL, DS_DG, and DS_DL all 0.00 (maximum delta 0.00); the same lookup reported Pangolin splice gain/loss values of 0.001 and -0.001, respectively. These results do not support a deleterious splice effect.
Sources
cspec ↗spliceai ↗

Statement

In silico

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

9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • A systematic approach to assessing the clinical significance of genetic variants.
    General variant-interpretation methodology paper; does not mention APC or c.2805C>T. It provides a general caution that a synonymous coding change can rarely exert pathogenicity by altering splicing (example: TECTA p.Leu1777Leu predicted ESE loss with exon 16 skipping demonstrated in patient mRNA). Consulted only as a caution that protein-neutral changes are not automatically inconsequential; no APC- or variant-specific splicing data are provided, and the APC VCEP decision tree plus a SpliceAI max delta score of 0.00 indicate no splicing-mediated consequence for c.2805C>T.
    Does not name this variant
    PMID 24033266 ↗
    Quoted passage
    For instance, a synonymous variant in exon 16 of TECTA, p.Leu1777Leu, may not be expected to be pathogenic because it does not alter the amino acid. However, it is predicted to lead to loss of an exonic splice enhancer binding site, has not been reported in large population studies, and has been reported to segregate with disease in 10 affected family members with autosomal dominant hearing loss (41). In addition, examination of mRNA from patient lymphocytes revealed skipping of exon 16, leading to an in-frame deletion in the amino acid sequence.

    Combining multiple lines of evidence to reach an overall interpretation, paragraph 2

  • ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
    No paper-specific finding is recorded.
    PMID 25645574 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Pathogenic mutations and rare variants of the APC gene identified in 75 Belgian patients with familial adenomatous polyposis by fluorescent enzymatic mutation detection (EMD).
    Michils G et al. · 2002
    This Belgian FAP/AFAP screening study explicitly lists the APC variant c.2805C>T as a synonymous TAC>TAT change at codon Y935 in exon 15 and classifies it as a polymorphism. It confirms the variant is protein-neutral (no amino-acid change, no truncation, no length alteration) and supports the conclusion that no loss-of-function or protein-length consequence exists for this variant.
    Names this variant
    PMID 12173026 ↗
    Quoted passage
    TAC?TAT | 15 | Y935Y | polymorphism

    Table 2, "Polymorphisms, unknown variants and missense mutations identified by EMD"

  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • APC-Associated Polyposis Conditions.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301519 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    No paper-specific finding is recorded.
    PMID 34012068 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 818 / 1,614,184 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 13 Likely benign · 8 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= 0.000506758; MAF= 0.05068%, 818/1614184 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000612701; MAF= 0.06127%, 723/1180020 alleles, homozygotes = 0); grpmax FAF= 0.00057528.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.000457252; MAF= 0.04573%, 129/282120 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000777049; MAF= 0.07770%, 100/128692 alleles, homozygotes = 0); grpmax FAF= 0.00068567.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0011399413744436, 21/18422 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (13 clinical laboratories) and as Benign (8 clinical laboratories). (ClinVarID = 136408)

In silico

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

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104567570, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.