5-112838220-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.2626C>T(p.Arg876Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R876R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 1.31

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 868 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112838220-C-T is Pathogenic according to our data. Variant chr5-112838220-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 216014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838220-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.2626C>T	p.Arg876Ter	stop_gained	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.2626C>T	p.Arg876Ter	stop_gained	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 07, 2021	PP1, PP4, PM2, PS4_moderate, PVS1_strong -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Mar 31, 2022	PVS1, PS4, PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 23, 2018	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2021	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 14961559, 15108288, 17411426, 26446593, 26625971, 33294277, 29367705, 24651453, 25623536, 25025766, 25695693, 25832318, 7833931, 18433509, 19029688, 20223039, 8187091, 19347965, 12581900, 23159591, 25307848, 20007843, 17653897, 14729851, 27146902, 10646887) -

Familial adenomatous polyposis 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	This sequence change creates a premature translational stop signal (p.Arg876*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1968 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 familial adenomatous polyposis (PMID: 8187091, 12581900, 14961559, 17411426, 19029688, 20223039). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216014). 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	Myriad Genetics, Inc.	May 04, 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	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 08, 2022	ACMG classification criteria: PVS1 strong, PS4 strong, PM2 moderate -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 07, 2021	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 07, 2018

The APC c.2626C>T; p.Arg876Ter variant (rs121913333) is reported in the literature in multiple individuals and families affected with familial adenomatous polyposis (De Rosa 2003, Ficari 2000, Friedl 2005, Hashimoto 2015, Kanter-Smoler 2008, Lagarde 2010, Mihalatos 2003, Miyaki 1994, Stekrova 2007, Stella 1994). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 216014) 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 truncate 1,968 amino acids and is predicted to result in a nonfunctional protein. Based on available information, this variant is considered to be pathogenic. References: De Rosa M et al. The mutation spectrum of the APC gene in FAP patients from southern Italy: detection of known and four novel mutations. Hum Mutat. 2003 Jun;21(6):655-6. Ficari F et al. APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis. Br J Cancer. 2000 Jan;82(2):348-53. Friedl W and Aretz S. Familial adenomatous polyposis: experience from a study of 1164 unrelated german polyposis patients. Hered Cancer Clin Pract. 2005 Sep 15;3(3):95-114. Hashimoto T et al. Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. Histopathology. 2015 Nov;67(5):689-98. Kanter-Smoler G et al. Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families. BMC Med. 2008 Apr 24;6:10. Lagarde A et al. Germline APC mutation spectrum derived from 863 genomic variations identified through a 15-year medical genetics service to French patients with FAP. J Med Genet. 2010 Oct;47(10):721-2. Mihalatos M et al. Novel mutations of the APC gene in familial adenomatous polyposis in Greek patients. Cancer Genet Cytogenet. 2003 Feb;141(1):65-70. 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. Stekrova J et al. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet. 2007 Apr 5;8:16. Stella A et al. Four novel mutations of the APC (adenomatous polyposis coli) gene in FAP patients. Hum Mol Genet. 1994 Sep;3(9):1687-8. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Arg876X variant has not been previously identified by our laboratory, but has been reported and in the literature in 36 out of 6228 proband chromosomes in individuals with FAP, HNPCC, and sporadic colorectal carcinoma. It was not found in any of the 400 control chromosomes (Friedl, Aretz 2005, Goranova 2011, Albuquerque 2010, Liu 2007, Miyaki 1994, Powell 1992, Plawksi 2008, Dymerska 2010, Ruruuchi 2000, Albuquerque 2002, Olschwang 1997, Stekrova 2007, Scheel 2010). The variant leads to a premature stop codon at position 876 which is predicted to cause premature truncation of the protein product and loss of function. Loss of function of the APC gene is an established mechanism of familial adenomatous polyposis. In summary based on the above information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The p.R876* pathogenic mutation (also known as c.2626C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2626. This changes the amino acid from an arginine to a stop codon within coding exon 15. This mutation has been previously reported in multiple individuals with familial adenomatous polyposis (FAP) syndrome (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Ficari F et al. Br. J. Cancer, 2000 Jan;82:348-53; De Rosa M et al. Hum. Mutat., 2003 Jun;21:655-6; Mihalatos M et al. Cancer Genet. Cytogenet., 2003 Feb;141:65-70; Kanter-Smoler G et al. BMC Med, 2008 Apr;6:10; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2; Zhang S et al. Gene, 2016 Feb;577:187-92; Ciavarella M et al. Eur. J. Hum. Genet. 2018 03;26(3):387-395). In addition to the clinical data 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. -

Neoplasm of the large intestine Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.99, 0.98
GERP RS		4.1

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: rs121913333; hg19: chr5-112173917; COSMIC: COSV57320538; COSMIC: COSV57320538;