5-112839978-AAG-A

Position:

• chr5-112839978-AAG-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.4393_4394del (p.Ser1465TrpfsTer3) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 4 probands meeting 4 phenotype points (PS4_Strong, [1316610, 28018803, 29998021, 28782241, 10768871]). The 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_Strong and PM2_supporting applied. (VCEP specifications version v2.1.0; date of approval 11/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA009520/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 5.78

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.4393_4394delAG	p.Ser1465fs	frameshift_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.4393_4394delAG	p.Ser1465fs	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11015_228+11016delAG		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	Frameshift variant predicted to result in protein truncation 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: 8281160, 11553046, 8162051, 28222664, 20924072, 12010888, 29367705, 15040027, 17653897, 8187091, 12378616, 24416237, 26840078, 8990002, 19509103, 24005794, 23159591, 27087319, 20434453, 15108288, 28018803, 9824584, 26681312, 29998021, 28782241, 33082750, 34199654, 32198650, 31547110, 31754633, 1316610, 10768871, 16134147, 8730280, 20223039) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2019	PVS1, PM2, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2019	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -

Familial adenomatous polyposis 1 Pathogenic:3 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Ser1465Trpfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1379 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 APC-related disease, including familial adenomatous polyposis and Gardner syndrome (PMID: 1316610, 10768871, 20685668, 26840078, 28018803, 28782241). This variant is also known as a 2-bp deletion (AG) at codon 1465, 4292-4293delGA and AG del. ClinVar contains an entry for this variant (Variation ID: 811). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 26, 2024	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP4;PM2;PVS1 -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 09, 2024

Variant summary: APC c.4393_4394delAG (p.Ser1465TrpfsX3) results in a premature termination codon and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant was absent in 251224 control chromosomes (gnomAD). c.4393_4394delAG has been reported in the literature in individuals affected with familial adenomatous polyposis, colorectal cancer and Gardner fibroma and has been found to segregate with disease in at least one family (e.g. deOliverira_2022, Miyoshi_1992, Schafer_2016, Neffa_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35534704, 1316610, 28018803, 29998021). ClinVar contains an entry for this variant (Variation ID: 811). Based on the evidence outlined above, the variant was classified as pathogenic. -

Periampullary adenoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2001

- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ser1465TrpfsX3 variant has been reported in the literature in 11/1576 probands with FAP or AFAP and extracolonic features (Enomoto_2000_10768871, Friedl_2005_20223039). The p.Ser1465TrpfsX3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1465 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the APC gene. In summary, based on the above information, this variant meets our criteria for pathogenicity. -

Colorectal cancer, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

Gardner syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2001

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2021

The c.4393_4394delAG pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 4393 to 4394, causing a translational frameshift with a predicted alternate stop codon (p.S1465Wfs*3). This mutation has been reported in numerous individuals and families diagnosed with FAP, including families presenting with the Gardner syndrome phenotype (Miyoshi Y et al. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6; Dobbie Z et al. J Med Genet. 1996 Apr;33(4):274-80; Friedl W and Aretz S. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Rivera B et al. Ann Oncol. 2011 Apr;22(4):903-9; Torrezan GT et al. Orphanet J Rare Dis. 2013;8:5; Schäfer M et al. European J Pediatr Surg Rep. 2016 Dec;4:17-21; Yu F et al. J. Cell. Mol. Med. 2018 Jan;22:152-162; Neffa F et al. J Gastrointest Oncol, 2018 Jun;9:553-559). An individual with unexplained polyposis was also found to be mosaic for this mutation (Ciavarella M et al. Eur J Hum Genet, 2018 03;26:387-395). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs387906234; hg19: chr5-112175675;