5-112839576-C-T

Variant names:

• chr5-112839576-C-T
• rs398123121
• NM_000038.6:c.3982C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.14

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 88 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 id is 92346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839576-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3982C>T	p.Gln1328*	stop_gained	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.3982C>T	p.Gln1328*	stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10604C>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

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. -

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. -

not provided Pathogenic:3

Oct 26, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

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 -

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) “With Pathogenic allele” 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 “InSiGHT Colon Cancer Database”, the variant was identified 4x with no classification. In the UMD-APC database the variant was identified 6x as “causal”. 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 laboratory’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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.99
GERP RS		6.0

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

LitVar

Other links and lift over

dbSNP: rs398123121; hg19: chr5-112175273; COSMIC: COSV57324976; COSMIC: COSV57324976;