rs587779353

chr5-112838792-ACAAT-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.3202_3205del(p.Ser1068GlyfsTer57) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000131 in 152,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1067Q) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.98

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 705 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838792-ACAAT-A is Pathogenic according to our data. Variant chr5-112838792-ACAAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 88914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838792-ACAAT-A is described in Lovd as [Pathogenic]. Variant chr5-112838792-ACAAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3202_3205del	p.Ser1068GlyfsTer57	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3202_3205del	p.Ser1068GlyfsTer57	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Ser1068Glyfs*57) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1776 amino acid(s) of the APC protein. This variant is present in population databases (rs587779353, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 8395941, 10646887, 19725996, 20333795, 23159591). It has also been observed to segregate with disease in related individuals. This variant is also known as 3202delTCAA or 3199_3202delCAAT. ClinVar contains an entry for this variant (Variation ID: 88914). 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	Baylor Genetics	Jul 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 08, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2023	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; This variant is associated with the following publications: (PMID: 8395941, 18393237, 19029688, 28445943, 21476993, 10646887, 20685668, 9950360, 8187091, 10768871, 8162022, 16317745, 20223039, 8990002, 18433509, 14961559, 20333795, 20924072, 12357334, 23159591, 19725996, 20007843, 21779980, 19444466, 9101302, 26556299, 30720243, 31589614, 36225625) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 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 mutant transcript 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 the Beta-catenin binding domain, EB1 binding domain, HDLG binding domain, and NLS domains (PMID: 17881494). This variant has been reported in families affected with familial adenomatous polyposis (PMID:8395941, 10646887, 19725996, 20333795, 23159591, 20924072). This variant has been identified in 2/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2023	The c.3202_3205delTCAA pathogenic mutation, located in coding exon 15 of the APC gene, results from the deletion of 4 nucleotides at positions 3202 to 3205, causing a translational frameshift with a predicted alternate stop codon (p.S1068Gfs*57). This mutation has been previously described in two unrelated probands. Eleven additional family members of one of the probands were also positive for the mutation, with clinical features including CHRPE, duodenal and gastric polyps, and epidermoid cysts (Paul P et al. Hum. Mol. Genet. 1993;2(7):925-31). In one meta analysis, this mutation was detected in 19/1164 German polyposis patients (Friedl W and Aretz S. Hered Cancer Clin Pract. 2005;3(3):95-114). In addition to the clinical information 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. -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 02, 2021

Variant summary: APC c.3202_3205delTCAA (p.Ser1068GlyfsX57) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250414 control chromosomes (gnomAD). c.3202_3205delTCAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Ficari_2000, Ripa_2002, Friedl_2005, Kerr_2013). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The APC p.Ser1068GlyfsX57 variant was identified in 40 of 4390 proband chromosomes (frequency: 0.009) from individuals or families with familial adenomatous polyposis (De Rosa_2003_14961559, Enomoto_2000_10768871, Friedl_2005_20223039, Kanter-Smoler_2008_18433509, Paul_1993_8395941, Plawski_2008_19029688, Ripa_2002_12357334, Rivera_2011_20924072, Sheng_2010_20333795, van der Luijt_1997_8990002, Wallis_1999_9950360). The variant was also identified in dbSNP (ID: rs587779353) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry, Invitae, Mayo, and previously reported by Mount Sinai), Clinvitae (5x as pathogenic), Cosmic (in large intestine and soft tissue), LOVD 3.0 (75x), UMD-LSDB (56x as causal), and Zhejiang Colon Cancer Database (16x). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in 3 individuals with familial adenomatous polyposis. 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.Ser1068GlyfsX57 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1068 and leads to a premature stop codon at position 1124. 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. -

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: rs587779353; hg19: chr5-112174489;