NM_000038.6:c.3982C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000038.6(APC):c.3982C>T(p.Gln1328*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1328Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.14

Publications

11 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: 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

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 798 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-112839576-C-T is Pathogenic according to our data. Variant chr5-112839576-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 92346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APC	NM_000038.6	MANE Select	c.3982C>T	p.Gln1328*	stop_gained	Exon 16 of 16	NP_000029.2
APC	NM_001407446.1		c.4066C>T	p.Gln1356*	stop_gained	Exon 16 of 16	NP_001394375.1
APC	NM_001354896.2		c.4036C>T	p.Gln1346*	stop_gained	Exon 17 of 17	NP_001341825.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
APC	ENST00000257430.9	TSL:5 MANE Select	c.3982C>T	p.Gln1328*	stop_gained	Exon 16 of 16	ENSP00000257430.4
APC	ENST00000508376.6	TSL:1	c.3982C>T	p.Gln1328*	stop_gained	Exon 17 of 17	ENSP00000427089.2
APC	ENST00000502371.3	TSL:1	n.*2180C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000484935.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000535

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:3

Mar 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 10, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln1328*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1516 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis the literature (PMID: 8395941, 9101302, 14961559, 20685668, 26900293). ClinVar contains an entry for this variant (Variation ID: 92346). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, internal data). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:3

Nov 30, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1_Strong, PS2, PM2, PP4

Apr 18, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple individuals with a personal and/or family history of adenomatous polyposis (PMID: 8395941, 9101302, 14961559); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20685668, 26900293, 14961559, 22810696, 9101302, 25851626, 21901162, 30897307, 8395941, 18199528)

Oct 26, 2012

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Pathogenic:1

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Carcinoma of colon

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The p.Gln1328X variant was identified in 6 of 192 proband chromosomes (frequency: 0.031) from Italian individuals or families with familial adenomatous polyposis (Paul 1993, De Rosa 2003, Gismondi 1997). The variant is listed in the dbSNP database (ID#: rs398123121) â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹ however no frequency information was provided. The variant was not found in 1000 Genomes Project, NHLBI Exome Sequencing Project (Exome Variant Server), or the Exome Aggregation Consortium (ExAC) databases. The variant was identified 2x by Emory Genetics in the ClinVar database classified as a pathogenic variant. In Clinvitae the variant is classified 1x as pathogenic; and was identified 20x in COSMIC (15x as somatic mutations: 11x from tumour and 9x from an unknown source). In the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, the variant was identified 4x with no classification. In the UMD-APC database the variant was identified 6x as â€šÃ„Ãºcausalâ€šÃ„Ã¹. The p.Gln1328X variant leads to a premature stop codon at position 1328, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

APC-related disorder

Pathogenic:1

Sep 16, 2022

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The APC c.3982C>T variant is predicted to result in premature protein termination (p.Gln1328*). This variant has been reported in many individuals with familial adenomatous polyposis coli (Table 1, Pedigree 1193, Paul et al. 1993. PubMed ID: 8395941; Table 1, De Rosa et al. 2003. PubMed ID: 14961559; Table 1, Gismondi et al. 1997. PubMed ID: 9101302; Supplement, Lagarde et al. 2010. PubMed ID: 20685668; Table 1, de Oliveira et al. 2019. PubMed ID: 30897307). It has also been reported in individuals with colorectal cancer (Table 3, Chang et al. 2016. PubMed ID: 26900293). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/92346/). Nonsense variants in APC are expected to be pathogenic. Although this variant occurs in the terminal exon of APC, pathogenic truncating variants have been reported downstream of this variant (The Human Gene Mutation Database, https://www.hgmd.cf.ac.uk; ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/). This variant is interpreted as pathogenic.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 12, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Q1328* pathogenic mutation (also known as c.3982C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3982. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation (also designated Q1328X) has been reported in multiple individuals with a clinical diagnosis of familial adenomatous polyposis (FAP) (de Oliveira JC et al. Cancer Med, 2019 May;8:2114-2122; De Rosa M et al. Hum. Mutat. 2003 Jun;21:655-6; Gismondi V et al. Hum. Mutat. 1997;9:370-3; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Paul P et al. Hum. Mol. Genet. 1993 Jul;2:925-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.90

PhyloP100

4.1

Vest4

0.99

GERP RS

6.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over