rs863224820

Positions:

• chr5-112775657-GA-G

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.453delA​(p.Glu152fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.57

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 5-112775657-GA-G is Pathogenic according to our data. Variant chr5-112775657-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 216848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112775657-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.453delA	p.Glu152fs	frameshift_variant	5/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.453delA	p.Glu152fs	frameshift_variant	5/16	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 26, 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	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2023	This sequence change creates a premature translational stop signal (p.Glu152Lysfs*18) 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 hepatoblastoma (PMID: 12702169, 20223039, 23575299, 23715166). ClinVar contains an entry for this variant (Variation ID: 216848). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	Frameshift 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 (Lek 2016); This variant is associated with the following publications: (PMID: 12702169, 28185118, 20223039, 29251405, 23575299, 32543227, 23715166) -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Glu152LysfsX18 variant was identified in 3 of 3892 proband chromosomes (frequency: 0.0008) from individuals or families with FAP (Friedl_2005, Heinitz_2003, Mankay_2017). The variant was also identified in the following databases: dbSNP (ID: rs863224820) as “With Pathogenic allele”, and in ClinVar (4x as pathogenic by Invitae, GeneDx, Ambry Genetics, Mayo Clinic, criteria provided). The variant was not identified in Cosmic, MutDB, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Glu152LysfsX18 variant was identified in a patient as co-occurring with a different germline missense variant E1317Q (Heinitz_2003). The p.Glu152LysfsX18 variant was observed in a young child (18 month) affected with hepatoblastoma (Gupta_2013), and a 12 year old girl from a FAP family who was diagnosed with extraintestinal malignancy (Rauch_2014). The c.453del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 152 and leads to a premature stop codon 18 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 FAP 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The c.453delA pathogenic mutation, located in coding exon 4 of the APC gene, results from a deletion of one nucleotide at nucleotide position 453, causing a translational frameshift with a predicted alternate stop codon (p.E152Kfs*18). This mutation has been detected in multiple patients with a clinical diagnosis of familial adenomatous polyposis (FAP) (Heinritz W et al. Clin. Genet. 2003 Apr; 63(4):325-7; Friedl W and Aretz S. Hered Cancer Clin Pract. 2005 Sep; 3(3):95-114; Mankaney G et al. Fam. Cancer. 2017 Feb; Pegues J et al. Ear Nose Throat J, 2020 Jun;:145561320934602). It has also been detected in a child who presented with multifocal hepatic neoplasia at 18 months of age (Gupta A et al. Am. J. Surg. Pathol. 2013 Jul; 37(7):1058-66) and in another child who was diagnosed with FAP at age 10 and presented with Cushing syndrome due to an adrenocortical carcinoma at age 12 (Rauch LB et al. J. Pediatr. Gastroenterol. Nutr. 2014 Feb; 58(2):e19-20). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: -28

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224820; hg19: chr5-112111354;