chr5-112819245-C-T

Variant names:

• chr5-112819245-C-T
• rs587779780
• NM_000038.6:c.1213C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):​c.1213C>T​(p.Arg405*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000372 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 3.98

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]

ACMG classification

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 rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1213C>T	p.Arg405*	stop_gained	Exon 10 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1213C>T	p.Arg405*	stop_gained	Exon 10 of 16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

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: 5 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

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: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

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:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 06, 2023

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: 25525159, 20223039, 30257133, 29901124, 1338764, 20685668, 15986289, 26681312, 33087929, 35189564) -

Nov 16, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Mar 25, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: PVS1, PM2, PS4:Moderate -

Familial adenomatous polyposis 1 Pathogenic:5

Jun 26, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 30, 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.Arg405*) in the APC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or altered 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 produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -

Apr 11, 2023

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 07, 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 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. -

Dec 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial multiple polyposis syndrome Pathogenic:1

Nov 09, 2023

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.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. -

Inherited polyposis and early onset colorectal cancer - germline testing Pathogenic:1

Sep 13, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PS4_Moderate,PM2_Supporting -

APC-related disorder Pathogenic:1

Apr 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
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

Other links and lift over

dbSNP: rs587779780; hg19: chr5-112154942; COSMIC: COSV57322404; COSMIC: COSV57322404;