Genetic Variant APC:p.1451 (chr5-112839942-CGA-AGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingB4_Supporting

The NM_000038.6(APC):c.4348_4350delCGAinsAGG (p.1451) variant causes a synonymous change. The gene APC is a tumor suppressor gene (CancerMine: 215 TSG, 264 oncogene, 89 driver citations). The gene APC is a known oncogene (CancerMine: 215 TSG, 264 oncogene, 89 driver citations). The gene APC is a cancer driver gene (CancerMine: 215 TSG, 264 oncogene, 89 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The variant position is a cancer hotspot (cancerhotspots.org) with 58 samples affected at this amino acid position.

Frequency

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 synonymous

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.21

Publications

0 publications found

Variant links:

Genes affected

APC (HGNC:583): (APC regulator of Wnt signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC Gene-Disease associations (from GenCC):

classic or attenuated familial adenomatous polyposis
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
desmoid tumor
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
familial adenomatous polyposis 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
gastric adenocarcinoma and proximal polyposis of the stomach
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Cenani-Lenz syndactyly syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

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new If you want to explore the variant's impact on the transcript NM_000038.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for APC are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (3)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 58, same AA change = 0; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 0 pathogenic, 0 benign; Variant does not impact splicing — splice-hotspot path not applicable
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant outside canonical splice sites (B4 supporting); Synonymous variant — splicing impact not confirmed absent; B4 supporting [-1]

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000038.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
APC NM_000038.6	MANE Select	c.4348_4350delCGAinsAGG p.1451	synonymous	N/A	Prot: NP_000029.2
APC NM_001407446.1		c.4432_4434delCGAinsAGG p.1479	synonymous	N/A	Prot: NP_001394375.1
APC NM_001354896.2		c.4402_4404delCGAinsAGG p.1469	synonymous	N/A	Prot: NP_001341825.1 UniProt: R4GMU6

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.4348_4350delCGAinsAGGp.1451

Exon rankN/A

synonymous

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.4432_4434delCGAinsAGGp.1479

Exon rankN/A

synonymous

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.4402_4404delCGAinsAGGp.1469

Exon rankN/A

synonymous

Prot: NP_001341825.1UniProt: R4GMU6

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
APC ENST00000257430.9	TSL:5MANE Select	c.4348_4350delCGAinsAGG p.1451	synonymous	N/A	Prot: ENSP00000257430.4 UniProt: P25054-1
APC ENST00000508376.6	TSL:1	c.4348_4350delCGAinsAGG p.1451	synonymous	N/A	Prot: ENSP00000427089.2 UniProt: P25054-1
APC ENST00000508624.5	TSL:1	n.3670_3672delCGAinsAGG	3_prime_UTR	Exon 17 of 17	Prot: ENSP00000424265.1 UniProt: E7EMH9

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.4348_4350delCGAinsAGGp.1451

Exon rankN/A

synonymous

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.4348_4350delCGAinsAGGp.1451

Exon rankN/A

synonymous

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000508624.5

TSL:1

HGVSc / HGVSpn.*3670_*3672delCGAinsAGG

Exon rankExon 17 of 17

3_prime_UTR

Prot: ENSP00000424265.1UniProt: E7EMH9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	3.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACGS-UK Somatic Oncogenicity v2025

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence