chr5-112801313-A-C

Variant names:

• chr5-112801313-A-C
• rs530670052
• NM_000038.6:c.764A>C
• APC p.His255Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_000038.6(APC):c.764A>C (p.His255Pro) variant causes a missense 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 allele was found at a cumulative frequency of 0.000000685 (AC=1) in the gnomAD database across 1,460,764 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000009. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.H255= (synonymous): Likely_benign (ClinVar VariationId 1101103, 2 stars); p.H255L: Uncertain_significance (ClinVar VariationId 3410081, 2 stars); p.H255R: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 236648)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09
• Publications: 2 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

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.

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 = 0.000001, AC = 1 — absent/extremely rare (O3 moderate [+2])

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.764A>C p.His255Pro	missense	Exon 8 of 16	Prot: NP_000029.2
	APC NM_001354906.2		c.-272A>C	5_prime_UTR_premature_start_codon_gain	Exon 8 of 17	Prot: NP_001341835.1
	APC NM_001407470.1		c.-272A>C	5_prime_UTR_premature_start_codon_gain	Exon 8 of 17	Prot: NP_001394399.1

APC NM_000038.6

MANE Select

HGVSc / HGVSpc.764A>Cp.His255Pro

Exon rankExon 8 of 16

missense

Prot: NP_000029.2

APC NM_001354906.2

HGVSc / HGVSpc.-272A>C

Exon rankExon 8 of 17

5_prime_UTR_premature_start_codon_gain

Prot: NP_001341835.1

APC NM_001407470.1

HGVSc / HGVSpc.-272A>C

Exon rankExon 8 of 17

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394399.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APC ENST00000257430.9	TSL:5MANE Select	c.764A>C p.His255Pro	missense	Exon 8 of 16	Prot: ENSP00000257430.4 UniProt:
	APC ENST00000508376.6	TSL:1	c.764A>C p.His255Pro	missense	Exon 9 of 17	Prot: ENSP00000427089.2 UniProt:
	APC ENST00000502371.3	TSL:1	n.764A>C	non_coding_transcript_exon	Exon 7 of 12	Prot: ENSP00000484935.2 UniProt:

APC ENST00000257430.9

TSL:5MANE Select

HGVSc / HGVSpc.764A>Cp.His255Pro

Exon rankExon 8 of 16

missense

Prot: ENSP00000257430.4UniProt: P25054-1

APC ENST00000508376.6

TSL:1

HGVSc / HGVSpc.764A>Cp.His255Pro

Exon rankExon 9 of 17

missense

Prot: ENSP00000427089.2UniProt: P25054-1

APC ENST00000502371.3

TSL:1

HGVSc / HGVSpn.764A>C

Exon rankExon 7 of 12

non_coding_transcript_exon

Prot: ENSP00000484935.2UniProt: A0A087X2F3

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: 6.85e-7	AC:1	Hom:0	AN:1460764	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	19
AlphaMissense	Benign	0.073
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.87	D
FuncVEP CTI	Benign	0.011
GPN-Star LLR	N/A	-4.7
GPN-Star score	N/A	4.7
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.46	D
Mutation Taster	N/A	68/32	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	2.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.51
Sift	Benign	0.081	T
Sift4G	Benign	0.31	T
Varity_R	N/A	0.14
VESM-3B	Benign	-2.1

Showing 29 of 29 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

dbSNP: rs530670052;

hg19: chr5-112137010;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar