rs863225332

chr5-112838397-T-TA

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.2804dup(p.Tyr935Ter) variant causes a stop gained, frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y935Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained, frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.06

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 831 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838397-T-TA is Pathogenic according to our data. Variant chr5-112838397-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217954.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.2804dup	p.Tyr935Ter	stop_gained, frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.2804dup	p.Tyr935Ter	stop_gained, frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 02, 2023	ClinVar contains an entry for this variant (Variation ID: 217954). This variant is also known as c.2803insA. This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 10090483, 20685668, 23159591, 28533537). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr935*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1909 amino acid(s) of the APC protein. 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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 25, 2016	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 10, 2022	PP4, PM2, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2018	This duplication of one nucleotide is denoted APC c.2804dupA at the cDNA level and p.Tyr935Ter (Y935X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTT[dupA]CAAT. The duplication creates a nonsense variant, which changes a Tyrosine to a premature stop codon, and is predicted to cause loss of normal protein function through protein truncation. Even though this nonsense variant occurs in the last exon of the gene, and nonsense-mediated decay is not expected to occur, it is significant since the last 1909 amino acids are no longer translated. APC c.2804dupA, previously reported as APC 2803insA, has been shown to result in a truncated protein by a protein truncation assay (Scarano 1999) and has been reported in association with familial adenomatous polyposis (FAP) (Scarano 1999, De Rosa 2003, Lagarde 2010, Kerr 2013, Kohda 2016, Pearlman 2016). This variant is considered 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.Tyr935X variant was identified in 1 of 80 proband chromosomes (frequency: 0.013) from individuals or families with FAP (De Rosa 2003). The variant was also identified in dbSNP (ID: rs863225332) as “With Pathogenic allele”, ClinVar (as pathogenic by Mayo and likely pathogenic by Counsyl), Clinvitae database (as pathogenic/likely pathogenic), COSMIC (3x large intestine carcinoma, 1x thyroid carcinoma), InSiGHT Colon Cancer Gene Variant Database (5x as pathogenic), and UMD (6x with a “causal” classification). This variant was not identified in Zhejiang Colon Cancer (LOVD), GeneInsight, MutDB, the 1000 Genomes Project, HAPMAP, the NHLBI GO Exome Sequencing Project, the genome Aggregation Database (beta, October 19th 2016), or the Exome Aggregation Consortium database (August 8th 2016) databases. The p.Tyr935X variant leads to a premature stop codon at position 935, which is predicted to lead to 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2022

The c.2804dupA pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 2804, causing a translational frameshift with a predicted alternate stop codon (p.Y935*). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1909 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This mutation has been detected in multiple individuals with familial adenomatous polyposis (FAP) (Scarano MI et al. Hum Mutat. 1999;13(3):256-7; Khan N et al. Sci Rep, 2017 May;7:2214; Ambry internal data). 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: rs863225332; hg19: chr5-112174094;