5-112838880-C-T

Variant names:

• chr5-112838880-C-T
• rs587783029
• NM_000038.6:c.3286C>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.3286C>T​(p.Gln1096*) 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:7
• Conservation: PhyloP100: 4.64

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 173 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838880-C-T is Pathogenic according to our data. Variant chr5-112838880-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 156475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838880-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.3286C>T	p.Gln1096*	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.3286C>T	p.Gln1096*	stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9908C>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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Jun 28, 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.Gln1096*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1748 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 (FAP) syndrome (PMID: 10077047, 19331226, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 156475). 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, Invitae). 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. -

May 08, 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. -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

May 09, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 16 of the APC gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the nuclear localization signal domains, beta-Catenin-, EB1-, and HDLG-binding sites (PMID: 17881494). This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 10077047, 19331226, 20223039, 20685668). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Apr 08, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1096* pathogenic mutation (also known as c.3286C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3286. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1748 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration is reported in multiple individuals with a clinical diagnosis of FAP or AFAP from a variety of ethnic backgrounds (Gebert JF et al. Ann. Surg.,1999 Mar; 229:350-61; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Borosenko V et al. Anticancer Res., 2009 Feb;29:711-5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Feb 04, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_Moderate, PM2_Supporting c.3286C>T, located in exon 16 of the APC gene is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay, p.(Gln1096*)(PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. This variant has been identified in several individuals affected with familial adenomatous polyposis (PMID: 10077047, PMID: 19331226, PMID: 20223039, PMID:20685668) (PS4_Moderate). To our knowledge, no functional studies have been reported for this variant. This variant has been reported in the ClinVar database (6x) and in the LOVD database (4x) as a pathogenic variant. Based on currently available information, the variant c.3286C>T is classified as a pathogenic variant according to ClinGen-APC Guidelines version 1.0. -

not provided Pathogenic:1

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.97, 0.97
GERP RS		5.6

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: rs587783029; hg19: chr5-112174577; COSMIC: COSV57336639; COSMIC: COSV57336639;