Variant classification summary

NM_001127510.3:c.3479C>A

APC · NP_001120982.1:p.(Thr1160Lys) · NM_001127510.3

GRCh37: chr5:112174770 C>A · GRCh38: chr5:112839073 C>A

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Thr1160Lys)

gnomAD AF

0.0002695250782242325 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): population allele frequency 0.048% in gnomAD v4.1 exceeds the >=0.001% benign threshold by ~48-fold in both gnomAD releases.

2

BP1 (Supporting): missense change outside the VCEP's excepted beta-catenin repeat (codons 1021-1035) is consistent with benign supporting evidence.

3

Overall: Likely Benign — BS1 (Strong) + BP1 (Supporting), no pathogenic criteria met (APC VCEP v2.1).

Final determination: Rule26: exactly one of BS1/BS2/BS3/BS4 met (Benign.Strong) → 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	Not applicable: p.(Thr1160Lys) is a missense substitution, and PVS1 is reserved for null variants (nonsense, frameshift, splice-site, or deletion).	cspec
PS1	Not met	Not met: no established Pathogenic or Likely Pathogenic APC missense produces p.Thr1160Lys; only codons 1026 and 1028 qualify.	cspec
PS2	Not assessed	Not assessed: no de novo observation with both parents tested was available for this variant.	cspec
PS3	Not assessed	Not assessed: no functional assay data (protein or RNA) for this specific variant was available.
PS4	Not assessed	Not assessed: insufficient individual-level phenotype detail was available to assign phenotype points.	cspec vcep_table_1_262 PMID:18199528
PM1	N/A	Not applicable: the APC VCEP designates PM1 (mutational hotspot) as not applicable for this gene.	cspec
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.02695% (435 alleles) far exceeds the <=0.0003% PM2 threshold.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 is not used under the APC VCEP because familial adenomatous polyposis is autosomal dominant.	cspec
PM4	N/A	Not applicable: p.Thr1160Lys is a missense substitution with no protein-length change, and the VCEP does not use PM4.	cspec vcep_table_1_262
PM5	Not met	Not met: no established Pathogenic or Likely Pathogenic missense variant at codon 1160; only codons 1026 and 1028 qualify.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no observation of this variant as de novo with parental relationships unconfirmed was available.	cspec
PP1	Not assessed	Not assessed: no pedigree or affected-relative data were available to establish co-segregation.	cspec
PP2	N/A	Not applicable: the APC VCEP marks PP2 as not applicable because missense variants are not a frequent APC disease mechanism.	cspec
PP3	Not met	Not met: SpliceAI predicts no splice impact (all four delta scores 0.00, below the 0.2 threshold).	cspec spliceai
PP4	N/A	Not applicable: phenotype and family-history evidence is captured through the PS4 specifications per the APC VCEP.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: PP5 is not used under the APC VCEP, and ClinVar has no expert-panel submission for this variant.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BA1	Not met	Not met: highest observed population allele frequency 0.048% is below the >=0.1% BA1 threshold.	cspec gnomad_v4
BS1	Met	Met (Strong): highest observed population allele frequency 0.048% exceeds the >=0.001% BS1 threshold in both gnomAD releases.	cspec gnomad_v2 gnomad_v4
BS2	Not met	Not met: zero homozygotes and no healthy-individual observations meeting the VCEP requirements (>=10 points) were available.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no protein functional assay data for this variant were available; the RNA-assay arm does not apply to missense changes.
BS4	Not assessed	Not assessed: no affected relative tested negative for this variant, and no non-segregation phenotype data were available.	cspec
BP1	Met	Met (Supporting): p.Thr1160Lys falls outside the excepted beta-catenin repeat (codons 1021-1035), where missense is generally benign in APC.	cspec
BP2	Not assessed	Not assessed: no qualifying co-occurring pathogenic APC variant or phase information was available.	cspec
BP3	N/A	Not applicable: the variant is a missense substitution, not an in-frame indel, and the VCEP does not use BP3.	cspec vcep_table_1_262
BP4	N/A	Not applicable: BP4 applies only to synonymous or intronic variants; c.3479C>A is a missense change.	cspec
BP5	Not assessed	Not assessed: no evidence of an alternate molecular diagnosis in a p.Thr1160Lys carrier was available.	cspec PMID:18199528
BP6	N/A	Not applicable: BP6 is not used under the APC VCEP, and ClinVar has no expert-panel benign classification for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants; this is a missense change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.