rs398123118

chr5-112838137-AAGAT-A

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.2547_2550del(p.Asp849GlufsTer11) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K848K) 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:12 U:1
• Conservation: PhyloP100: 9.60

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 889 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838137-AAGAT-A is Pathogenic according to our data. Variant chr5-112838137-AAGAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 92342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838137-AAGAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.2547_2550del	p.Asp849GlufsTer11	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.2547_2550del	p.Asp849GlufsTer11	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:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 17, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2021	This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in affected individuals with familial adenomatous polyposis in the published literature (PMIDs: 8187091 (1994), 17963004 (2007), 20223039 (2005), 20685668 (2010), 21643010 (2011), 29406563 (2018), and 30897307 (2019)). This variant has also been confirmed as de novo in three familial adenomatous polyposis cases (PMIDs: 12357334 (2002) and 31069152 (2019)). Therefore, the variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 04, 2023	ClinVar contains an entry for this variant (Variation ID: 92342). For these reasons, this variant has been classified as Pathogenic. 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. 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. This premature translational stop signal has been observed in individuals with clinical features of familial adenomatosis polyposis (PMID: 12357334, 17963004, 20223039, 20685668, 29406563, 30897307; Invitae). 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.Asp849Glufs*11) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1995 amino acid(s) of the APC protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 04, 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 05, 2022	ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderated, PM6 moderated, PP1 supporting -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt several important c-terminal domains of the APC protein including the beta-catenin binding domain, SAMP-repeats, basic domain, EB1 binding domain, and HDLG domain (PMID: 11257105). This variant has been reported in individuals affected with familial adenomatous polyposis (FAP) (PMID: 20685668, 21643010, 31069152) as well as in individuals affected with colon polyposis or desmoid tumors (PMID: 29406563, 30897307). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2014	This variant is denoted APC c.2547_2550delTAGA at the cDNA level and p.Asp849GlufsX11 (D849EfsX11) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA{TAGA}AGTT. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 849 in exon 16, and creates a premature stop codon at position 11 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. APC 2547_2550delTAGA, previously reported as 2547del4, has been observed in association with Familial Adenomatous Polyposis (Ripa 2002, Friedl 2005). We therefore consider this mutation to be pathogenic. and is indicative of a Familial Adenomatous Polyposis (FAP)-associated condition, which includes classic FAP and attenuated FAP (AFAP). These autosomal dominant conditions predispose individuals to the development of many polyps, colorectal cancer, and other cancers. AFAP is distinguished from classic FAP primarily by the difference in polyp burden and age at presentation. Individuals with classic FAP may develop hundreds to thousands of adenomatous polyps by age 35 and, on average, are diagnosed with colon cancer by the age of 39. The age-related risk for colon cancer in untreated individuals is 7% by age 21, 87% by age 45, and 93% by age 50 (Jasperson 2010). Individuals with AFAP develop an average of about 30 polyps and are typically diagnosed with colon cancer between ages 50 and 55. Other cancer risks in individuals with FAP and AFAP include 5% risk for duodenal or periampullary cancer, and in FAP less than or equal to a 2% risk for stomach, thyroid, pancreatic, brain (typically medulloblastoma), and liver (hepatoblastoma) cancers, while AFAP has less than or equal to a 2% risk for stomach, thyroid, and pancreatic cancers (Jasperson 2012). Upper gastrointestinal tract polyps and fundic gland polyps are present in most cases of classic FAP and AFAP; other findings include desmoid tumors, osteomas, epidermoid cysts, and fibromas. Approximately 20-25% of individuals with an APC mutation have a de novo, rather than inherited, mutation. The variant is found in APC panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 25, 2022	The c.2547_2550delTAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 2547 to 2550, causing a translational frameshift with a predicted alternate stop codon (p.D849Efs*11). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1995 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data).This mutation has been reported in multiple individuals with familial adenomatous polyposis (FAP) including some individuals with extra colonic manifestations including desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and hepatoblastoma (Ripa R et al. Eur J Hum Genet, 2002 Oct;10:631-7; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; De la Fuente MK et al. Dis Colon Rectum, 2007 Dec;50:2142-8; Lagarde A et al. J Med Genet, 2010 Oct;47:721-2; Rohlin A et al. Oncogene, 2011 Dec;30:4977-89; Yanus GA et al. Clin Genet, 2018 05;93:1015-1021; Morcrette G et al. Oncoimmunology Mar;8:e1583547; de Oliveira JC et al. Cancer Med, 2019 05;8:2114-2122). 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. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 09, 2018

The APC c.2547_2550delTAGA; p.Asp849fs variant (rs398123118) has been described in several individuals and families affected with familial adenomatous polyposis (FAP; Friedl 2005, Miyaki 1994, Ripa 2002). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 92342) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Based on available information, this variant is considered pathogenic. REFERENCES Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Friedl W et al. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Miyaki M et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 1994 Jun 1;54(11):3011-20. Ripa R et al. De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet. 2002 Oct;10(10):631-7. -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 22, 2018

Variant summary: APC c.2547_2550delTAGA (p.Asp849GlufsX11) 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 245936 control chromosomes (in gnomAD). c.2547_2550delTAGA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Miyaki 1994, Friedl 2005, Rohlin 2011), segregation with the disease was also described (Ripa 2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

APC-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The APC c.2547_2550delTAGA variant is predicted to result in a frameshift and premature protein termination (p.Asp849Glufs*11). This variant has been reported in several individuals and families with Familial Adenomatous Polyposis (examples, Ripa et al 2002. PubMed ID: 12357334; de Oliveira JC et al 2019. PubMed ID: 30897307; Lagarde A et al 2010. PubMed ID: 20685668). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/92342/). This variant is interpreted as pathogenic. -

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: rs398123118; hg19: chr5-112173834;