5-112840329-A-T

Variant names:

• chr5-112840329-A-T
• rs587781935
• NM_000038.6:c.4735A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2_Supporting PS4_Supporting BP1 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.4735A>T variant in APC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid position 1579 (p.Ile1579Phe). β-catenin regulated transcription activity assay in SW480 cells showed increased β-catenin regulated transcription activity indicating that this variant impacts protein function (PS3_Supporting, PMID:18199528). This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 points (PS4_Supporting [Ambry Genetics, Invitae, GeneDx]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_Supporting, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584253/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 8.95
• Publications: 4 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: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.4735A>T	p.Ile1579Phe	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.4735A>T	p.Ile1579Phe	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11357A>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:2

May 16, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6(APC):c.4735A>T variant in APC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid position 1579 (p.Ile1579Phe). β-catenin regulated transcription activity assay in SW480 cells showed increased β-catenin regulated transcription activity indicating that this variant impacts protein function (PS3_Supporting, PMID: 18199528). This variant has been reported in 3 probands meeting phenotypic criteria, resulting in a total phenotype score of 1.5 points (PS4_Supporting [Ambry Genetics, Invitae, GeneDx]). The variant has been reported in 1 additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). APC, in which the variant was identified, is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant is a VUS for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BP1, PS3_Supporting, PS4_Supporting, PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

May 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1579 of the APC protein (p.Ile1579Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 246402). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 24, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1579F variant (also known as c.4735A>T), located in coding exon 15 of the APC gene, results from an A to T substitution at nucleotide position 4735. The isoleucine at codon 1579 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-related disease (Ambry internal data; Personal communication). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

not provided Uncertain:1

Jul 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528, 27377421) -

Classic or attenuated familial adenomatous polyposis Uncertain:1

Oct 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces isoleucine with phenylalanine at codon 1579 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		8.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.84
MutPred		0.79		Gain of glycosylation at S1581 (P = 0.0994);Gain of glycosylation at S1581 (P = 0.0994);
MVP		0.98
ClinPred		0.95	D
GERP RS		6.2
Varity_R		0.74
gMVP		0.84
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587781935; hg19: chr5-112176026;