5-112792494-C-T

Variant names:

• chr5-112792494-C-T
• rs397515734
• NM_000038.6:c.694C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000038.6:c.694C>T p.(Arg232Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 7 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least 10 probands meeting phenotypic criteria, resulting in a total phenotype score of > 4 (PS4, [PMID:1316610, 20223039, 7524601, 21110124, 19279422 and several more]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA012693/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1 O:1
• Conservation: PhyloP100: 1.57
• Publications: 47 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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.694C>T	p.Arg232*	stop_gained	Exon 7 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.694C>T	p.Arg232*	stop_gained	Exon 7 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460336 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111116

Other (OTH) AF: 0.00 AC: 0 AN: 60288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:6 Uncertain:1

Dec 04, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.694C>T (p.Arg232*) variant in the APC gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with familial adenomatous polyposis (PMID: 1316610, 8187091, 8730280, 8990002, 9664575, 9950360, 12007223, 12173026, 15108286, 16134147, 17963004, 20223039, 20649969, 20924072, 21110124, 23159591). The c.694C>T (p.Arg232*) variant in the APC gene is classified as pathogenic. -

Jan 11, 2025

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.Arg232*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). 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: 1316610, 20223039, 20685668, 24735542). ClinVar contains an entry for this variant (Variation ID: 42248). For these reasons, this variant has been classified as Pathogenic. -

Oct 09, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6:c.694C>T p.(Arg232Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 7 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in at least 10 probands meeting phenotypic criteria, resulting in a total phenotype score of > 4 (PS4, [PMID: 1316610, 20223039, 7524601, 21110124, 19279422 and several more]). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1, PS4 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

Sep 17, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

not provided Pathogenic:5

Apr 04, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP4, PM2, PS4_moderate, PVS1 -

Oct 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.694C>T (p.Arg232*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals with familial adenomatous polyposis (FAP) (PMID: 17963004 (2007), 18433509 (2008), 20924072 (2011), 26300997 (2015), 30897307 (2019), 35189564 (2022)) and pancreatic cancer (PMID: 29961768 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.Arg232X variant was identified in the literature in 18 of 7060 proband chromosomes (frequency: 0.003) from individuals with familial adenomatous polyposis (Dobbie 1996, Fostira 2010, Friedle 2005, Han 2011, Kerr 2012, Michils 2002, Miyaki 1994, Miyoshi 1992, Olschwang 1993, Van der Luijt 1997, Wallis 1999); and was found to segregate with disease in one of the families studied, increasing the likelihood that it is pathogenic (Olschwang 1993). This variant was also identified in HGMD, “InSiGHT Colon Cancer Database”, and 66 times in UMD. The p.Arg232X variant leads to a premature stop codon at position 232, 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 is classified as pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 16134147, 20223039, 20649969, 20924072, 12173026, 9342373, 25525159, 12007223, 17963004, 1316610, 22886683, 9664575, 21110124, 15108286, 24033266, 26917275, 26900293, 26300997, 26446593, 29961768, 30897307, 31269945, 31447099, 35189564, 36964972, 34897210) -

Familial multiple polyposis syndrome Pathogenic:2

Jan 31, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg232X nonsense variant has previously been reported as pathogenic in the l iterature. This variant has been identified as a germline change in at least 15 individuals with clinical features of Familial Adenomatous Polyposis syndrome (M iyoshi 1992, Olschwang 1997, Kraus 1998, Gavert 2002, Michils 2002, Bisgaard 200 4, Friedl 2005, Aceto 2005, De la Fuente 2007, Fostira 2010, Han 2011, Rivera 20 11) and in one individual with clinical diagnosis of Attenuated Familial Adenoma tous Polyposis (AFAP) (Rivera 2011). The presence of a heterozygous pathogenic v ariant in APC is consistent with a diagnosis of Familial Adenomatous Polyposis ( FAP) syndrome. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 11, 2023

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 7 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 1316610, 1338764, 7524601, 7833149, 8381580, 10077047, 11668620, 12007223, 12010888, 12173026, 15108286, 17963004, 18433509, 19279422, 21110124, 23116752, 23159591) and a family affected with colorectal cancer and polyps (PMID: 24735542). 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. -

Jun 23, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R232* pathogenic mutation (also known as c.694C>T), located in coding exon 6 of the APC gene, results from a C to T substitution at nucleotide position 694. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation is well described in the literature and has been reported in multiple individuals diagnosed with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. 1992 May;89(10):4452-6; Friedl W and Aretz S. Hered. Cancer Clin. Pract. 2005 Sep;3(3):95-114; Kanter-Smoler G et al. BMC Med. 2008 Apr;6:10; Zhang Y et al. Biochem. Biophys. Res. Commun. 2014 May;447(3):503-7; Simbolo M et al. Hered. Cancer Clin. Pract. 2015 Aug;13(1):18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		1.6
Vest4		0.97
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs397515734; hg19: chr5-112128191; COSMIC: COSV57320753;