Is APC p.Glu2655fs (c.7964_7965del) pathogenic?

APC p.Glu2655fs (c.79647965del) is classified Uncertain significance in APC (ClinVar, Expert panel, 5 submitters; last evaluated 2025-05-19). Very rare (popmax 0.00017%, nfe); Associated with familial adenomatous polyposis 1.

What condition is associated with APC p.Glu2655fs (c.7964_7965del)?

APC p.Glu2655fs (c.7964_7965del) is associated with familial adenomatous polyposis 1, hereditary neoplastic syndrome (ClinVar).

How common is APC p.Glu2655fs (c.7964_7965del) in the general population?

APC p.Glu2655fs (c.7964_7965del) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Familial adenomatous polyposis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

APC p.Glu2655fs

c.7964_7965del · rs2149997043 · VCV1361956

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

familial adenomatous polyposis 1

ClinGen expert panel — InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Uncertain Significance for familial adenomatous polyposis 1. Applied ACMG criteria (verbatim):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000038.6(APC):c.7964_7965del (p.Glu2655fs) variant in APC is a frameshift variant located downstream of codon 2645, therefore PVS1 is not applicable based on the ACMG/AMP criteria specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was observed in a 30 years old patient with 3 to 5 histologically confirmed adenomas, a desmoid and a positive FAP family history, who also carried, in unknown phase, NM_000038.6(APC):c.426_427del (p.Leu143fs) (classified as Pathogenic in ClinVar - Variation ID: 142574) (BP2 not met; internal data Labcorp Genetics (formerly Invitae)). The variant has been reported in 4 additional probands without a colorectal cancer/polyposis associated phenotype worth 0.5 healthy individual points in total (BS2 not met, internal data Ambry and Labcorp Genetics (formerly Invitae)). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: criteria PM2_Supporting applied (VCEP specifications v2.1.0; date of approval 11/24/2023).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,846 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,688 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: APC
Protein: p.Glu2655fs
Coding: c.7964_7965del
MANE Select: NM_000038
dbSNP: rs2149997043
Type: Microsatellite
Location: chr5:112843556 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2655: the 'basic region' region; the 'interaction with dlg1' region

Full APC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial adenomatous polyposis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Familial adenomatous polyposis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

APC p.Glu2655_Asp2656insTer Pathogenic ★ same residue
APC p.Glu2655Gly Uncertain significance ★ same residue
APC p.Glu2655Val Uncertain significance ★ same residue
APC p.Glu2655= Likely benign ★ same residue
APC c.531+5_531+8del Likely pathogenic ★★★ same condition
APC p.Gln2600fs Likely pathogenic ★★★ same condition
APC p.Leu370del Uncertain significance ★★★ same condition
APC p.Ala2122dup Benign ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/apc-p-glu2655fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown