rs1554085081

Positions:

• chr5-112839117-C-T

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.3523C>T​(p.Gln1175Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.14

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 151 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839117-C-T is Pathogenic according to our data. Variant chr5-112839117-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 537459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839117-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.3523C>T	p.Gln1175Ter	stop_gained	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3523C>T	p.Gln1175Ter	stop_gained	16/16	5	NM_000038.6	ENSP00000257430	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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:4

Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Oct 10, 2019	This variant creates a premature termination codon. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of APC is a well-established mechanism of disease for FAP (De la Fuente 2007, Lagarde 2010). This variant has been reported in the literature in individuals with FAP (Miyoshi 1992, Andresen 2009). This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PM2; PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 19, 2019	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 has been reported in individuals affected with familial adenomatous polyposis (PMID: 1316610, 19444466, 27158207). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Gln1175*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1669 amino acids 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 13, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 03, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 04, 2018

The APC c.3523C>T; p.Gln1175Ter variant is reported in the literature in multiple individuals affected with familial adenomatous polyposis (Andresen 2009, Jung 2016, Michils 2002, Miyoshi 1992). This variant is reported as pathogenic in ClinVar (Variation ID: 537459), 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 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. Additionally, other nonsense variants downstream of this variant have been reported in individuals with familial adenomatous polyposis and are considered pathogenic (Andresen 2009, Jung 2016, Michils 2002, Miyoshi 1992). Based on available information, the p.Gln1175Ter variant is considered to be pathogenic. References: Andresen PA et al. APC mutation spectrum of Norwegian familial adenomatous polyposis families: high ratio of novel mutations. J Cancer Res Clin Oncol. 2009 Oct;135(10):1463-70. Jung SM et al. Clinicopathological features of familial adenomatous polyposis in Korean patients. World J Gastroenterol. 2016 May 7;22(17):4380-8. Michils G et al. Pathogenic mutations and rare variants of the APC gene identified in 75 Belgian patients with familial adenomatous polyposis by fluorescent enzymatic mutation detection (EMD). Eur J Hum Genet. 2002 Sep;10(9):505-10. Miyoshi Y et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2015

The p.Q1175* pathogenic mutation (also known as c.3523C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 3523. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This pathogenic mutation has been reported in multiple individuals diagnosed with FAP or AFAP (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A.1992 May; 89(10):4452-6; Michils G et al. Eur. J. Hum. Genet. 2002 Sep; 10(9):505-10.). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.99
GERP RS		5.8

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: rs1554085081; hg19: chr5-112174814; COSMIC: COSV57325534; COSMIC: COSV57325534;