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NM_001127510.3:c.7594C>T
p.His2532Tyr · APC
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 · v2.1
0%
complete
Final classification
Likely Benign
BS1BP1
APC
c.7594C>T
p.His2532Tyr
missense · exon 17
Gene context NCBI Gene ↗ OncoKB ↗

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.

This variant

The APC p.(His2532Tyr) missense change is evaluated in the context of APC's tumor-suppressor role in restraining Wnt signaling and its association with autosomal-dominant familial adenomatous polyposis.

Transcript
NM_001127510.3
HGVS · transcript:coding
NM_001127510.3:c.7594C>T
GRCh38
chr5:112843188 C>T
GRCh37
chr5:112178885 C>T
Likely Benign: BS1 (strong) satisfies APC VCEP Rule26; BP1 (supporting) is also met.
Classification rationale
BS1BP1 Likely Benign
APC c.7594C>T missense · exon 17

BS1 strong: gnomAD v4.1 Popmax FAF of 1.064e-05 exceeds the APC VCEP threshold of 1e-05. BP1 supporting: residue 2532 lies outside the APC VCEP exception at codons 1021-1035.

BS1 + BP1 → Likely Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_001127510.3 · variants mapped to exon structure
APC NM_001127510.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
BS1 strong Benign
Met, strong: gnomAD v4.1 Popmax FAF is 1.064e-05, exceeding the APC VCEP BS1 threshold of 1e-05.
The APC InSiGHT VCEP specifies BS1 as gnomAD Popmax Filtering Allele Frequency >=0.00001 (0.001%).gnomAD v4.1 reports a Popmax filtering allele frequency of 1.064e-05 (0.001064%), exceeding the VCEP threshold.
cspec ↗gnomad_v4 ↗
BP1 supporting Benign
Met, Supporting: APC residue 2532 lies outside the VCEP BP1 exception at codons 1021-1035 in the beta-catenin-binding domain.
The APC VCEP rule states that BP1 is applicable except for missense variants located in codons 1021-1035, the first 15-amino-acid repeat of the beta-catenin-binding domain.The assessed missense variant is NP_001120982.1:p.(His2532Tyr), placing the altered residue at codon 2532, outside the exception.
cspec ↗
Assessed · not applied · 4 not met · 11 not assessed
Pathogenic
PS1 Not met: p.(His2532Tyr) does not match either VCEP-listed likely pathogenic APC missense change, p.(Asn1026Ser) or p.(Ser1028Arg).
PS2 Not assessed: no proband-level parental testing or phenotype-based de novo score is available to compare with the APC VCEP threshold of >=1 score.
PS3 Not assessed: APC VCEP requires damaging RNA or protein assay evidence, but no variant-specific functional assay result is available for p.His2532Tyr.
PS4 Not assessed: no curated phenotype-point total, case-control enrichment estimate, or sufficient unrelated affected-person phenotype data is available for this exact variant.
PM2 Not met: non-cancer gnomAD v2.1 exomes show AF 1.27043e-05 with allele count 3, above the APC PM2 threshold of 3e-06.
PM5 Not assessed: no p.His2532 comparator was verified, and comparator retrieval ended with HTTP 429 before absence could be established.
PM6 Not assessed: no assumed-de-novo parental testing result or de novo score is available to compare with the APC VCEP threshold of 0.5 score.
PP1 Not assessed: no affected relatives, family segregation data, or informative meiosis count is available to compare with the APC VCEP minimum of 3 meioses.
PP3 Not met: REVEL 0.452 is below the calibrated supporting PP3 threshold of 0.644 for this missense variant.
Benign
BA1 Not met: gnomAD v4.1 Popmax FAF is 1.064e-05, below the APC VCEP BA1 threshold of 0.001.
BS2 Not assessed: gnomAD reports 0 homozygotes, but no individual-level healthy-control data are available to calculate the APC VCEP point thresholds.
BS3 Not assessed: APC VCEP requires a qualifying no-effect RNA or β-catenin transcription assay, but no variant-specific benign functional result is available.
BS4 Not assessed: no affected noncarrier or phenotype-point score is available to compare with the APC VCEP BS4 threshold of 0.5 phenotype points.
BP2 Not assessed: no documented trans observation, second pathogenic APC variant, phase result, or qualifying three-variant recurrence is available.
BP5 Not assessed: no qualifying alternate pathogenic gene finding and no documented colorectal polyposis phenotype are available for BP5.
N/A · 11 PVS1 · PM1 · PM3 · PM4 · PP2 · PP4 · PP5 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.3637e-05; MAF= 0.00136%, 22/1613254 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00577e-05; MAF= 0.00401%, 3/74892 alleles, homozygotes = 0); grpmax FAF= 1.064e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.77258e-05; MAF= 0.00177%, 5/282074 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00577e-05; MAF= 0.00401%, 1/24964 alleles, homozygotes = 0); grpmax FAF= 7.05e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0014% · 22 / 1,613,254
0 hom · FAF 0.0011%
African/African American
3 / 74,892
0.004%
Remaining individuals
1 / 62,464
0.0016%
European (non-Finnish)
18 / 1,179,330
0.0015%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0018% · 5 / 282,074
0 hom · FAF 0.00071%
African/African American
1 / 24,964
0.004%
European (non-Finnish)
4 / 128,496
0.0031%
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 220176)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.452. BayesDel score = 0.0745716.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57339290, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
11598466 ↗ Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR
25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR
25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende CLINVAR
27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR