Variant chr5-112819245-C-T details in Genebe, Genetics Data Aggregator

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 links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-112819245-C-T is Pathogenic according to our data. Variant chr5-112819245-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 127275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819245-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1213C>T	p.Arg405Ter	stop_gained	10/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1213C>T	p.Arg405Ter	stop_gained	10/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	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: 25525159, 20223039, 30257133, 29901124, 1338764, 20685668, 15986289, 26681312, 33087929, 35189564) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	The APC c.1213C>T; p.Arg405Ter variant (rs587779780) has been reported in multiple individuals with familial adenomatous polyposis (Friedl 2005, Nagase 1992). It is listed as pathogenic in ClinVar (Variation ID: 127275), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, this variant is considered pathogenic. References: Friedl W et al. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005; 3(3):95-114. Nagase H et al. Screening for germ-line mutations in familial adenomatous polyposis patients: 61 new patients and a summary of 150 unrelated patients. Hum Mutat. 1992; 1(6):467-73. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 16, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Arg405X variant has been previously reported in at least 4 of 2632 proband chromosomes in individuals with FAP ( Nagase 1992, Friedl 2005). In addition, this variant has been identified as a frequent mutation in somatic colorectal cancer (Harismendy 2011, Powell 1992). The p.Arg405X variant leads to a premature stop codon at position 405, 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 for FAP. In summary, based on the above information, this variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	APC: PVS1, PM2, PS4:Moderate -

Familial adenomatous polyposis 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change creates a premature translational stop signal (p.Arg405*) in the APC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. 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: 1338764, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 127275). Studies have shown that this premature translational stop signal results in skipping of exon 10 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 11, 2023	The c.1213C>T variant in APC has previously been reported in multiple individuals with typical or attenuated familial adenomatous polyposis [PMID: 1338764,20223039, 28135145, 35189564, 30257133, 29901124, 15986289, 26681312, 33087929], and it has been deposited in ClinVar [ClinVar ID: 127275] as Pathogenic by multiple submitters. The c.1213C>T variant is observed in 1 allele (0.00018% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 andv3.1.2, TOPMed Freeze 8) suggesting it is not a common benign variant in the populations represented in those databases. The c.1213C>T variant is located in exon 10 of this 16-exon gene, predicted to incorporate a premature termination codon (p.(Arg405Ter)), and is expected to result in loss-of-function via nonsense-mediated decay. Multiple loss-of-function variants that are downstream to the c.1213C>T variant have been reported in the literature and public variant repositories in individuals with familial adenomatous polyposis. Based on available evidence this heterozygous c.1213C>T p.(Arg405Ter) variant identified in APC is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 28, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 10, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2021	The p.R405* pathogenic mutation (also known as c.1213C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 1213. This changes the amino acid from an arginine to a stop codon within coding exon 9. This mutation has been reported in multiple individuals diagnosed with typical or attenuated familial adenomatous polyposis (FAP) (Nagase H et al. Hum Mutat, 1992;1:467-73; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095; Pang M et al. Mol Med Rep, 2018 Aug;18:1423-1432). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 07, 2023	This variant changes 1 nucleotide in exon 10 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial adenomatous polyposis and attenuated familial adenomatous polyposis (PMID: 1338764, 15952110, 15986289, 20223039, 20685668, 28135145, 29901124). 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. -

Familial multiple polyposis syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 09, 2023

Variant summary: APC c.1213C>T (p.Arg405X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250352 control chromosomes. c.1213C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Lee_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35189564). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

APC-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2024

The APC c.1213C>T variant is predicted to result in premature protein termination (p.Arg405*). This variant has been reported in multiple individuals with familial adenomatous polyposis coli (Table 1, Nagase et al. 1992. PubMed ID: 1338764; Table S1, Friedl et al. 2005. PubMed ID: 20223039; Gentner et al. 2005. PubMed ID: 15986289; Table 1, Lee et al. 2022. PubMed ID: 35189564). 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 in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127275/). Nonsense variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

A;A;A

Vest4

0.98, 0.98

GERP RS

5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

chr5-112819245-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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