rs864622228

chr5-112841415-CCAGA-C

Variant summary

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

The NM_000038.6(APC):c.5826_5829del(p.Asp1942GlufsTer27) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1941P) has been classified as Likely 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: 5.18

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 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 143 pathogenic variants in the truncated region.
• PP5: Variant 5-112841415-CCAGA-C is Pathogenic according to our data. Variant chr5-112841415-CCAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 219743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841415-CCAGA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5826_5829del	p.Asp1942GlufsTer27	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5826_5829del	p.Asp1942GlufsTer27	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 28, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	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 in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8968744, 15108286, 25074465, 11001924, 29625052) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2019	The APC c.5826_5829delCAGA; p.Asp1942fs variant (rs864622228), also known as 5824delGACA and 5844_5847del4, is reported in the literature in multiple individuals and several large families affected with familial adenomatous polyposis (Bisgaard 2004, Lamlum 2000, Scott 1996, Vieira 2015). This variant is reported in ClinVar (Variation ID: 219743), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the APC gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein missing the last 902 amino acids. Based on available information, this variant is considered to be pathogenic. References: Bisgaard ML et al. Mutation analysis of the adenomatous polyposis coli (APC) gene in Danish patients with familial adenomatous polyposis (FAP). Hum Mutat. 2004 May;23(5):522. Lamlum H et al. Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet. 2000 Sep 22;9(15):2215-21. Scott RJ et al. Familial infiltrative fibromatosis (desmoid tumours) (MIM135290) caused by a recurrent 3' APC gene mutation. Hum Mol Genet. 1996 Dec;5(12):1921-4. Vieira J et al. Identification of previously unrecognized FAP in children with Gardner fibroma. Eur J Hum Genet. 2015 May;23(5):715-8. -

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2023	This sequence change creates a premature translational stop signal (p.Asp1942Glufs*27) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 902 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 a personal or family history of desmoid tumors or familial adenomatous polyposis, Gardner fibroma with suspected desmoid tumor, and/or polyposis (PMID: 8968744, 11001924, 15108286, 25074465). It has also been observed to segregate with disease in related individuals. This variant is also known as 5824delGACA and 5844_5847del4. ClinVar contains an entry for this variant (Variation ID: 219743). This variant disrupts a region of the APC protein in which other variant(s) (p.Asn1979Thrfs*64) have been determined to be pathogenic (PMID: 9824584, 20434453). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 15, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Desmoid disease, hereditary Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2023

The c.5826_5829delCAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 5826 to 5829, causing a translational frameshift with a predicted alternate stop codon (p.D1942Efs*27). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). This alteration was also identified in an infant with Gardner fibroma and in this individual's sister who had hepatoblastoma; other family members had a history of colon polyposis and colorectal cancer (Vieira J et al. Eur. J. Hum. Genet., 2015 May;23:715-8). In addition, this alteration was detected in a family that included ten individuals with >100 colon adenomas (Bisgaard ML et al. Hum. Mutat., 2004 May;23:522). Epidermoid cysts, osteomas, duodenal adenomas and desmoid tumors were also reported in this family (Bisgaard ML et al. Hum. Mutat., 2004 May;23:522). In another study, this alteration (referred to as a 4 bp deletion at nucleotides 5844–5847 (codon 1962)) was detected in three unrelated families that had at least two individuals with desmoid tumors with otherwise variable presentation of colorectal polyposis and colorectal cancer (Scott RJ et al. Hum. Mol. Genet., 1996 Dec;5:1921-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, 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: rs864622228; hg19: chr5-112177112;