5-112839733-C-T

Variant names:

• chr5-112839733-C-T
• rs876660713
• NM_000038.6:c.4139C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2_Supporting PS4_Moderate BP1

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.4139C>T variant in APC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid position 1380 (p.Thr1380Ile). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 points (PS4_Moderate [Ambry Genetics, Invitae]). The variant has been reported in 2 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one unaffected individual with a positive family history for colorectal polyposis (Invitae). 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: criteria BP1, PS4_Moderate, PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10578369/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.57
• Publications: 1 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.

• 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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.4139C>T	p.Thr1380Ile	missense	Exon 16 of 16	NP_000029.2
	APC	NM_001407446.1		c.4223C>T	p.Thr1408Ile	missense	Exon 16 of 16	NP_001394375.1
	APC	NM_001354896.2		c.4193C>T	p.Thr1398Ile	missense	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.4139C>T	p.Thr1380Ile	missense	Exon 16 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.4139C>T	p.Thr1380Ile	missense	Exon 17 of 17	ENSP00000427089.2
	APC	ENST00000502371.3	TSL:1	n.*2337C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1 Uncertain:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1380 of the APC protein (p.Thr1380Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial adenomatosis polyposis (internal data). ClinVar contains an entry for this variant (Variation ID: 233890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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.4139C>T variant in APC is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid position 1380 (p.Thr1380Ile). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 points (PS4_Moderate [Ambry Genetics, Invitae]). The variant has been reported in 2 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and one unaffected individual with a positive family history for colorectal polyposis (Invitae). 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: criteria BP1, PS4_Moderate, PM2_Supporting applied (VCEP specifications v2.0.3; date of approval 7/24/2023).

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 03, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1380I variant (also known as c.4139C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 4139. The threonine at codon 1380 is replaced by isoleucine, an amino acid with similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with APC-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

not provided Uncertain:1

Jun 01, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted APC c.4139C>T at the cDNA level, p.Thr1380Ile (T1380I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported has a somatic variant in a serous endometrial tumor (Castonguay 2014). APC Thr1380Ile was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1380Ile occurs at a position that is conserved across species and is located in within the 20-amino acid repeat beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Thr1380Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.75		Gain of sheet (P = 0.0344)
MVP		0.99
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.82
Mutation Taster		=35/65	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: rs876660713; hg19: chr5-112175430; COSMIC: COSV57390031;