5-112840254-GA-GAA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):c.4666dup(p.Thr1556AsnfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1554E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 5.54

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 252 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112840254-G-GA is Pathogenic according to our data. Variant chr5-112840254-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 428112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4666dup	p.Thr1556AsnfsTer3	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4666dup	p.Thr1556AsnfsTer3	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 11, 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	National Molecular Genetics Centre of Cancer Research, N.N. Alexandrov National Cancer Centre of Belarus	May 30, 2018	Detected in patient with clinical features of Gardner syndrome. Emory Genetics Laboratory Classification Definitions Pathogenic: a. Variants predicted to result in the loss of protein function in a gene for which this is a known mechanism of disease (may or may not have been previously reported in patients with disease) 1. frameshift (an insertion or deletion that is not a multiple of 3 nucleotides). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 08, 2023	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. 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. Experimental studies have shown that this premature translational stop signal affects APC function (PMID: 14633595). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 428112). This variant is also known as 4663insA. This premature translational stop signal has been observed in individuals with familial adenomatous polyposis (PMID: 9101302, 11852337, 17411426, 19029688, 20685668, 20924072, 21110124, 26511139). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1556Asnfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1288 amino acid(s) of the APC protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genetics Bochum, Ruhr University Bochum	Dec 08, 2021	ACMG criteria used to clasify this variant: PVS1, PM2, PS4 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 20, 2022	The c.4666dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 4666, causing a translational frameshift with a predicted alternate stop codon (p.T1556Nfs*3). This mutation has been reported in two unrelated Italian polyposis patients (Gismondi V et al. Hum. Mutat. 1997;9(4):370-3), and a Spanish patient diagnosed with osteoma who had no family history of cancer (Rivera B et al. Ann Oncol. 2011 Apr;22(4):903-9). It was also observed in a two-year-old boy with a Gardner-associated fibroma, lumbar paraspinal desmoid and multiple other lesions; both parents tested negative for the mutation (Kiessling P et al. Cold Spring Harb. Mol. Case Stud. 2019 Apr;5(2)). Of note, this alteration is also designated as 4663insA in published literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 01, 2021	This variant inserts 1 nucleotide in exon 16 of the APC gene, creating a frameshift and 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 performed for this variant. This variant has been reported in individuals affected with more than 10 patients with familial adenomatous polyposis (PMID: 15024739, 17411426, 22987206, 16134147, 11852337, 18433509, 20223039, 20685668, 24750145, 30696621). 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. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The APC p.Thr1556AsnfsX3 variant was identified in 18 of 4600 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancer, and was not identified in 150 control chromosomes from healthy individuals (Aceto 2005, Friedl 2005, Han 2011, Kanter-Smoler 2008, Kohoutova 2002, Liu 2007, Out 2015, Palacio_Rua 2014, Plawski 2008, Rivera 2011, Schwarzova 2013, Stekrova 2007, Vandrovcova 2004), however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant was also identified in HGMD, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database” and UMD (7X as a un validated variant). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Thr1556AsnfsX3 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1556 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in 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 meets our laboratory’s criteria to be classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

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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: rs587783031; hg19: chr5-112175951;