BS1_Strong is met: the variant has a gnomAD v2.1 grpmax filtering allele frequency of 0.063% (0.00063466), approximately 63-fold above the VCEP BS1 threshold of ≥0.001% (0.00001). This is also supported by gnomAD v4.1 with 1,256 alleles (grpmax FAF 0.095%) including one homozygote.1 BP1_Supporting is met: the variant is a missense change (p.Arg99Trp) in APC, a gene where truncating variants are the predominant disease mechanism. Codon 99 is outside the excluded region (codons 1021–1035, the first 15-amino acid repeat of the β-catenin binding domain).2 Per the APC VCEP rules for combining criteria, the fulfillment of one Benign-Strong criterion (BS1) reaches a classification of Likely Benign. The additional BP1_Supporting criterion reinforces this assessment.3 This variant is classified as Benign in ClinVar (Variation ID: 135695) with review status 'reviewed by expert panel,' consistent with the VCEP-based assessment here.4
APC
Final classification
Likely Benign
APC c.295C>T · p.Arg99Trp
APC
BS1_Strong is met: the variant has a gnomAD v2.1 grpmax filtering allele frequency of 0.063% (0.00063466), approximately 63-fold above the VCEP BS1 threshold of ≥0.001% (0.00001). This is also supported by gnomAD v4.1 with 1,256 alleles (grpmax FAF 0.095%) including one homozygote.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 v2.1 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BS1 strong benign, BP1 supporting benign, BP6 supporting benign; maps to Likely Benign.
Classification rationale
BS1BP1BP6
Likely Benign
APC c.295C>T
BS1 + BP1 + BP6
→
Likely Benign
2
cspec ↗vcep_apc_specifications_supplementary_material_v2
3
vcep_apc_rules_for_combining_criteria_v2
Gene diagram
· NM_001127510.3 · variants mapped to exon structure
APC
NM_001127510.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
The VCEP BS1 threshold is gnomAD Popmax Filtering AF ≥ 0.001% (0.00001). The gnomAD v2.1 grpmax FAF is 0.063% (0.00063466), approximately 63-fold above the BS1 threshold. Additionally, gnomAD v4.1 shows 1,256 alleles including 1 homozygote (grpmax FAF 0.095%), further supporting that this variant is too common in population databases for a fully penetrant APC-associated disorder.
gnomAD v2.1 grpmax FAF: 0.00063466 (0.063%) >> VCEP BS1 threshold 0.001%gnomAD v4.1: 1256 alleles
✓
BP1
supporting
Benign
APC is a gene where truncating (loss-of-function) variants are the predominant disease mechanism. The variant p.Arg99Trp is a missense change at codon 99, which lies outside the excluded region (codons 1021–1035, the first 15-amino acid repeat of the β-catenin binding domain). BP1 is applicable per VCEP rules.
APC VCEP: BP1 applicable to missense variants except codons 1021-1035Codon 99 is outside the excluded β-catenin binding domain repeat region
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic or likely pathogenic missense variant resulting in the same amino acid change (p.Arg99Trp) has been identified.
PS2
No de novo observations with confirmed parentage are available for this variant in the evidence.
PS3
No variant-specific functional data available.
PS4
No proband or phenotype data available to assess prevalence in affected individuals versus controls.
PM2
The VCEP PM2_Supporting threshold for allele count > 1 requires allele frequency ≤ 0.0003% (0.000003).
PM5
No known pathogenic or likely pathogenic missense variant at codon 99 (p.Arg99) exists.
PM6
No assumed de novo observations (without confirmed parentage) are available for this variant.
PP1
No co-segregation data available.
PP3
The APC VCEP restricts PP3 for missense variants to in silico splicing predictors only.
Benign
BA1
The VCEP BA1 threshold is gnomAD Popmax Filtering AF ≥ 0.1% (0.001).
BS2
No individual-level healthy phenotype data meeting VCEP criteria is available.
BS3
No functional studies demonstrating no damaging effect are available.
BS4
No non-segregation data available.
BP2
The variant has not been observed in trans with a pathogenic or likely pathogenic APC variant, nor has it been observed ≥3 times in unknown phase with different P/LP APC variants.
BP5
No alternate genetic basis for colorectal polyposis has been identified in association with this variant.
N/A · 7
PVS1 · PM1 · PP2 · PP4 · PP5 · BP4 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000778229; MAF= 0.07782%, 1256/1613920 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000997442; MAF= 0.09974%, 1177/1180018 alleles, homozygotes = 1); grpmax FAF= 0.00094937.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000399511; MAF= 0.03995%, 113/282846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000735465; MAF= 0.07355%, 95/129170 alleles, homozygotes = 0); grpmax FAF= 0.00063466.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027150304083405736, 5/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.078%
· 1256 / 1,613,920
1 hom · FAF 0.095%
1 hom · FAF 0.095%
European (non-Finnish) 1177 / 1,180,018 |
0.1% 1 hom |
Remaining individuals 47 / 62,480 |
0.075% |
African/African American 22 / 74,880 |
0.029% |
Admixed American 5 / 59,982 |
0.0083% |
European (Finnish) 3 / 64,000 |
0.0047% |
East Asian 2 / 44,886 |
0.0045% |
+ 4 not observed (Amish, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.04%
· 113 / 282,846
0 hom · FAF 0.063%
0 hom · FAF 0.063%
European (non-Finnish) 95 / 129,170 |
0.074% |
African/African American 9 / 24,968 |
0.036% |
Remaining individuals 2 / 7,224 |
0.028% |
European (Finnish) 3 / 25,118 |
0.012% |
Admixed American 3 / 35,436 |
0.0085% |
East Asian 1 / 19,944 |
0.005% |
+ 2 not observed (Ashkenazi Jewish, South Asian)
gnomAD Canada 🇨🇦
0.027%
· 5 / 18,416
0 hom · FAF 0.035%
0 hom · FAF 0.035%
African/African American 2 / 1,020 |
0.2% |
European (non-Finnish) 3 / 11,738 |
0.026% |
+ 7 not observed (Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
ClinVar
This variant is present in ClinVar (Variation ID: 135695); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.587. BayesDel score = 0.275108.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57367627, n = 14 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links