Variant classification summary

NM_001127510.3:c.295C>T

APC · NP_001120982.1:p.(Arg99Trp) · NM_001127510.3

GRCh37: chr5:112102960 C>T · GRCh38: chr5:112767263 C>T

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong benign BP1 supporting benign BP6 supporting benign

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Arg99Trp)

gnomAD AF

0.0007782294041836027 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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).

3

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.

4

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.

Final determination: Rule19 in the 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 is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense variant (c.295C>T, p.Arg99Trp). PVS1 is reserved for null variants (nonsense, frameshift, canonical splice) per the APC VCEP Figure 1 decision tree. This variant does not fall into any PVS1 bucket.	vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1	Not met	No previously established pathogenic or likely pathogenic missense variant resulting in the same amino acid change (p.Arg99Trp) has been identified. The only VCEP-recognized LP missense variants in APC are c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg), both at codons distant from codon 99.	cspec
PS2	Not met	No de novo observations with confirmed parentage are available for this variant in the evidence.
PS3	Not met	No variant-specific functional data available. The variant (codon 99) lies outside the APC β-catenin binding domain (codons 959–2129) where protein functional assays could be applicable per VCEP rules. No RNA assay data exists, and OncoKB reports no variant-specific reviewed functional evidence.	oncokb cspec
PS4	Not met	No proband or phenotype data available to assess prevalence in affected individuals versus controls. No phenotype points can be assigned per VCEP Table 1.
PS5	N/A	PS5 is not defined in the APC VCEP framework and is not a standard ACMG/AMP 2015 criterion.
PM1	N/A	The APC VCEP states PM1 is not applicable. No mutational hotspots or critical functional domains without benign variation have been established for APC.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	The VCEP PM2_Supporting threshold for allele count > 1 requires allele frequency ≤ 0.0003% (0.000003). This variant has gnomAD v2.1 AF of 0.04% (113/282,846 alleles), far exceeding the threshold. The variant is too common in population databases to qualify as rare in controls.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	No known pathogenic or likely pathogenic missense variant at codon 99 (p.Arg99) exists. The only VCEP-recognized LP missense variants in APC are at codons 1026 (p.Asn1026Ser) and 1028 (p.Ser1028Arg). No comparator missense variant at the same residue meets PM5 criteria.	cspec pm5_candidates clinvar
PM6	Not met	No assumed de novo observations (without confirmed parentage) are available for this variant.
PP1	Not met	No co-segregation data available. No family studies with meiotic segregation counts are present in the evidence.
PP2	N/A	The APC VCEP states PP2 is not applicable. Missense variants are not a frequent mechanism of disease in APC; truncating variants are the predominant pathogenic mechanism.	cspec
PP3	Not met	The APC VCEP restricts PP3 for missense variants to in silico splicing predictors only. SpliceAI predicts no significant splice impact (max delta score = 0.07), and no other splicing predictors suggest a deleterious splicing effect. Computational prediction models for conservation or evolution are not used per VCEP rules.	spliceai cspec
PP4	N/A	The APC VCEP states PP4 is not applicable. The patient's phenotype or family history specificity is already captured by the PS4 specifications.	cspec
PP5	N/A	The APC VCEP states PP5 is not for use, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The VCEP BA1 threshold is gnomAD Popmax Filtering AF ≥ 0.1% (0.001). The gnomAD v2.1 grpmax FAF is 0.063% (0.00063466), which is below the BA1 threshold. The gnomAD v4.1 grpmax FAF of 0.095% (0.00094937) also falls below the threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Met	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 gnomad_v4 cspec
BS2	Not met	No individual-level healthy phenotype data meeting VCEP criteria is available. The VCEP requires ≥10 points for healthy individuals (age ≥50, <5 adenomatous polyps, absence of Table 1 features) or ≥2 homozygous observations. The gnomAD v4.1 single homozygote is insufficient for BS2 (threshold is ≥2). The VCEP explicitly states gnomAD non-cancer dataset cannot be used to count heterozygous healthy individuals.	gnomad_v4 cspec
BS3	Not met	No functional studies demonstrating no damaging effect are available. The variant at codon 99 lies outside the APC β-catenin binding domain (codons 959–2129), where protein-level functional assays could be applicable per VCEP BS3_Supporting. No RNA assay data in constitutional patient samples exists for this missense variant.	cspec
BS4	Not met	No non-segregation data available. No affected family members without the variant have been reported with quantifiable phenotype points.
BP1	Met	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.	cspec vcep_apc_specifications_supplementary_material_v2
BP2	Not met	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.
BP4	N/A	The APC VCEP explicitly states BP4 is not applicable for missense variants. BP4 is reserved for synonymous or intronic variants where multiple in silico splicing predictors suggest no impact.	cspec
BP5	Not met	No alternate genetic basis for colorectal polyposis has been identified in association with this variant. The VCEP requires a (likely) pathogenic variant in another adenomatous polyposis gene (POLD1, POLE, MUTYH, NTHL1, MSH3, or mismatch repair genes) for BP5 application.
BP6	Met	Expert panel ClinVar expert panel classified as Benign.	cspec clinvar
BP7	N/A	BP7 is reserved for synonymous (silent) or intronic variants at or beyond +7/−21 splice positions. This variant (c.295C>T) is a missense substitution and does not meet BP7 applicability criteria.	cspec

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