5-112838007-C-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.2413C>T(p.Arg805*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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. R805R) 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:12O:2

Conservation

PhyloP100: 1.67

Publications

40 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 1426 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-112838007-C-T is Pathogenic according to our data. Variant chr5-112838007-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 127281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.2413C>T	p.Arg805*	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 link	c.2413C>T	p.Arg805*	stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1 link	n.228+9035C>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 01, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial multiple polyposis syndrome

Pathogenic:2

Sep 01, 2015

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 15, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: APC c.2413C>T (p.Arg805X) results in a premature termination codon located in the last exon, which is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein, removing the basic domain (amino acids 2224-2575; IPR009234) and the EB-1 binding domain (amino acid 2670-2843; IPR009232). Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250860 control chromosomes (gnomAD). c.2413C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Dobbie_1996, Iaquinto_2008, deOliveira_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Familial adenomatous polyposis 1

Pathogenic:2

Jul 31, 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.Arg805*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2039 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 (PMID: 8730280, 19531215, 20223039, 20649969, 20924072, 30897307). ClinVar contains an entry for this variant (Variation ID: 127281). 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 04, 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. -

Desmoid disease, hereditary

Pathogenic:1

Oct 15, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 8730280, 30897307; ClinVar 127281] -

Classic or attenuated familial adenomatous polyposis

Pathogenic:1

Jul 09, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2413C>T (p.Arg805*) variant in the APC gene is located on the exon 16 and is predicted to introduce a premature translation termination codon (p.Arg805*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 30897307, 31113927, 26446593, 19029688, 20649969). Loss-of-function variants of APC are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with familial adenomatous polyposis/colorectal cancer (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 127281). The variant is absent in the general population database (gnomAD). Therefore, the c.2413C>T (p.Arg805*) variant of APC has been classified as pathogenic. -

APC-related disorder

Pathogenic:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The APC c.2413C>T variant is predicted to result in premature protein termination (p.Arg805*). This variant has been reported in individuals with adenomatous polyposis coli (Table 1, Dobbie et al. 1996. PubMed ID: 8730280; Tables 1 and 4, de Oliveira et al. 2019. PubMed ID: 30897307; Table 1, Lee et al. 2022. PubMed ID: 35189564). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127281/). Nonsense variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Mar 21, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R805* pathogenic mutation (also known as c.2413C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2413. This changes the amino acid from an arginine 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 257 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 variant was previously described in an individual with polyposis and a family history of colorectal cancer (Dobbie Z et al. J. Med. Genet. 1996 Apr; 33(4):274-80). It was also seen in two individuals diagnosed with familial adenomatous polyposis (FAP) (Gutierrez Sanchez LH et al. Gastrointest. Endosc. 2018 Mar;87(3):648-656.e3). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach;C5679615:APC-related attenuated familial adenomatous polyposis

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 02-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.83

PhyloP100

1.7

Vest4

0.94, 0.93

GERP RS

4.4

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over