NM_000038.6:c.4350A>C

Variant names:

• chr5-112839944-A-C
• NM_000038.6:c.4350A>C
• APC p.Arg1450Arg

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingB4_Strong

The NM_000038.6(APC):c.4350A>C (p.Arg1450Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850
• Publications: 0 publications found

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

ENSG00000258864 (HGNC:):

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: Likely_benign. The variant received -1 points.

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 with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APC NM_000038.6	MANE Select	c.4350A>C p.Arg1450Arg	synonymous	Exon 16 of 16	Prot: NP_000029.2
	APC NM_001407446.1		c.4434A>C p.Arg1478Arg	synonymous	Exon 16 of 16	Prot: NP_001394375.1
	APC NM_001354896.2		c.4404A>C p.Arg1468Arg	synonymous	Exon 17 of 17	Prot: NP_001341825.1 UniProt:

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.4350A>Cp.Arg1450Arg

Exon rankExon 16 of 16

synonymous

Prot: NP_000029.2

APC NM_001407446.1

HGVSc / HGVSpc.4434A>Cp.Arg1478Arg

Exon rankExon 16 of 16

synonymous

Prot: NP_001394375.1

APC NM_001354896.2

HGVSc / HGVSpc.4404A>Cp.Arg1468Arg

Exon rankExon 17 of 17

synonymous

Prot: NP_001341825.1UniProt: R4GMU6

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APC ENST00000257430.9	TSL:5MANE Select	c.4350A>C p.Arg1450Arg	synonymous	Exon 16 of 16	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.4350A>C p.Arg1450Arg	synonymous	Exon 17 of 17	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000508624.5	TSL:1	n.*3672A>C	3_prime_UTR	Exon 17 of 17	Prot: ENSP00000424265.1 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.4350A>Cp.Arg1450Arg

Exon rankExon 16 of 16

synonymous

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.4350A>Cp.Arg1450Arg

Exon rankExon 17 of 17

synonymous

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000508624.5

TSL:1

HGVSc / HGVSpn.*3672A>C

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	14
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.8
DANN	Benign	0.83
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
PhyloP100	Benign	0.85
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

hg19: chr5-112175641;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar