5-112780895-C-T

Variant names:

• chr5-112780895-C-T
• rs587781392
• NM_000038.6:c.637C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.637C>T​(p.Arg213*) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 2.74
• Publications: 61 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112780895-C-T is Pathogenic according to our data. Variant chr5-112780895-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 140952.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	c.637C>T	p.Arg213*	stop_gained	Exon 6 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.637C>T	p.Arg213*	stop_gained	Exon 6 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Nov 19, 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.Arg213*) 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 and colon cancer (PMID: 1316610, 10094547, 17411426, 20223039, 20685668, 26681312). ClinVar contains an entry for this variant (Variation ID: 140952). For these reasons, this variant has been classified as Pathogenic. -

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 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jun 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.637C>T (p.Arg213*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals with familial adenomatous polyposis (PMID: 30897307 (2019), 22790147 (2012), 20685668 (2010), 20223039 (2005), 15857185 (2005), 15024739 (2004), 1316610 (1992)). 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. -

Sep 01, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM2, PVS1 -

Feb 12, 2024

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: 1316610, 26659639, 25525159, 15024739, 11960572, 15857185, 22790147, 22987206, 27087319, 15300853, 26917275, 26138249, 25248397, 25986922, 26681312, 29419868, 20685668, 20223039, 29367705, 31069152, 11933206, 17411426, 10094547, 34259353, 33309985, 34897210) -

Familial multiple polyposis syndrome Pathogenic:1

Apr 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg213X variant in APC has been reported in >15 individuals with APC-assoc iated cancers (Miyoshi 1992, Giarola 1999, Stekrova 2006, Friedl 2005, Garcia-L azano 2005, Lagarde 2010, Susswein 2016) and was absent from large population st udies. This variant has been reported as a somatic variant in >90 tumor samples from various cancer types, including colorectal cancer (The Catalogue of Somatic Mutations in Cancer, https://cancer.sanger.ac.uk/cosmic). This variant has also been reported in ClinVar (Variant ID: 140952). This nonsense variant leads to a premature termination codon at position 213, which is predicted to lead to a tr uncated or absent protein. Heterozygous loss of function of the APC gene is an e stablished disease mechanism in individuals with familial adenomatous polyposis (FAP). In summary, this variant meets criteria to be classified as pathogenic fo r FAP in an autosomal dominant manner based upon predicted impact to the protein , presence in affected individuals, and absence in the general population. ACMG/ AMP Criteria applied: PVS1; PS4; PM2. -

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

- -

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 APC p.Arg213X variant was identified in 17 of 3498 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Friedl 2005, Giarola 1999, Kanter-Smoler 2008, Kohoutova 2002, Miyoshi 1992, Rivera 2011, Stekrova 2007, Vandrovcova 2004) and was not identified in 206 control chromosomes from healthy individuals (Kohoutova 2002, Stekrova 2007). The variant was also identified HGMD, COSMIC, “InSiGHT Colon Cancer Database”, “Zhejiang Colon Cancer Database”, the ClinVar database (classified as a pathogenic variant by Ambry Genetics), GeneInsight (1X, classified as “pathogenic”) and UMD (97X as a unclassified variant). The p.Arg213X variant leads to a premature stop codon at position 213, 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. Furthermore, this position has been shown to cause a very severe phenotype with early onset of the disease (Vandrovcova 2004). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 28, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R213* pathogenic mutation (also known as c.637C>T), located in coding exon 5 of the APC gene, results from a C to T substitution at nucleotide position 637. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been identified in multiple patients with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May 15;89(10):4452-6; Garcia-Lozano JR et al. Genet. Test. 2005 Spring;9(1):37-40; Friedl W et al. Hered. Cancer Clin. Pract. 2005 Sep 15;3(3):95-114); Stekrova J et al. BMC Med. Genet. 2007 Apr;8:16; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Morcrette G et al. Oncoimmunology Mar;8:e1583547; de Oliveira JC et al. Cancer Med, 2019 05;8:2114-2122). This pathogenic mutation has also been reported as a de novo mutation in one FAP patient who had over 1000 polyps (Kanter-Smoler G et al. BMC Med. 2008 Apr 24;6:10). 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 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	0.62
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		2.7
Vest4		0.96, 0.96
GERP RS		3.7
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
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: rs587781392; hg19: chr5-112116592; COSMIC: COSV57321978; COSMIC: COSV57321978;