5-112827194-C-T

Variant names:

• chr5-112827194-C-T
• rs137854580
• NM_000038.6:c.1495C>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.1495C>T​(p.Arg499*) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: 1.56

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112827194-C-T is Pathogenic according to our data. Variant chr5-112827194-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112827194-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1495C>T	p.Arg499*	stop_gained	Exon 12 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1495C>T	p.Arg499*	stop_gained	Exon 12 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.-21C>T		upstream_gene_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:5

Apr 05, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg499*) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). 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: 8381580, 9487968, 20223039, 20685668, 21779980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 824). For these reasons, this variant has been classified as Pathogenic. -

Nov 26, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:3

Feb 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.1495C>T (p.Arg499*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals affected with familial adenomatous polyposis (FAP) or a related polyposis condition (PMIDs: 37542411 (2023), 36084716 (2023), 35979026 (2022), 35296888 (2022), 35014770 (2022), 33094510 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Feb 03, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12486240, 26650777, 31543384, 25525159, 20649969, 20223039, 23263490, 8381580, 12173026, 26613750, 27705013, 26917275, 26837502, 28135145, 28944238, 31118792, 35979026, 35296888, 33094510, 23159591, 21779980, 20924072, 20685668, 17963004, 12007223, 37542411, 36084716, 35014770, 9487968, 18433509) -

Hereditary cancer-predisposing syndrome Pathogenic:3

May 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R499* pathogenic mutation (also known as c.1495C>T), located in coding exon 11 of the APC gene, results from a C to T substitution at nucleotide position 1495. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation has been described in many patients and families with familial adenomatous polyposis (FAP) (Olschwang S et al. Am. J. Hum. Genet. 1993 Feb;52:273-9; Friedl W et al. Hered Cancer Clin Pract 2005 Sep;3:95-114; Kanter-Smoler G et al. BMC Med 2008 Apr;6:10; Fostira F et al. BMC Cancer 2010 Jul;10:389; Lagarde A et al. J. Med. Genet. 2010 Oct;47(10):721-2; Tsukanov AS et al. Russ J Genet. 2017 53(3):369-375). In one study of 136 Spanish classic FAP families, there appeared to be an association with desmoid tumors in patients who carried mutations in codon 499 (Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Feb 28, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 12 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial adenomatous polyposis (PMID: 8381580, 9487968, 10077047, 12007223, 12010888, 12173026, 12486240, 15024739, 15951963, 18433509, 20223039, 20649969, 20685668, 20924072, 21779980, 23159591, 25590978). It has been shown that this variant segregates with familial adenomatous polyposis (PMID: 9487968). 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. -

Feb 10, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2_Supporting, PP1 c.1495C>T, located in exon 12 of the APC gene, is a nonsense variant, p.(Arg499*), located between codon 49 and 2645 (PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, no functional studies have been reported for this variant. This variant has been reported in multiple individuals with familial adenomatous polyposis from different families (internal data and PMIDs: 9487968, 20649969, 20223039, 8381580, 18433509, 20685668, among others) (PS4). It has been shown that this variant segregates with familial adenomatous polyposis (PMID: 9487968) (PP1). This variant has been reported in ClinVar (13x pathogenic) and LOVD (33x pathogenic) databases. Based on currently available information, the variant c.1495C>T should be considered a pathogenic variant. -

Familial multiple polyposis syndrome Pathogenic:2

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.1495C>T (p.Arg499X) 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 251260 control chromosomes. c.1495C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Mankaney_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35979026). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.Arg499* variant was identified in 20 of 4340 proband chromosomes (frequency: 0.005) from individuals or families with Familial Adenomatous Polyposis (Olschwang 1993, Friedl 2005, Lagarde 2010 20685668, Jarry 2011). The variant was identified in dbSNP (rs137854580) as “with pathogenic, uncertain significance allele”, ClinVar (interpreted as "pathogenic" by Invitae, Ambry Genetics and 7 others ), LOVD 3.0 (observed 33x) and UMD-LSDB (observed 35x). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.1495C>T variant leads to a premature stop codon at position 499, 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. -

Gardner syndrome Pathogenic:1

Nov 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

APC-Associated Polyposis Disorders Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 02-07-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.98, 0.98
GERP RS		5.0

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: rs137854580; hg19: chr5-112162891; COSMIC: COSV57322064; COSMIC: COSV57322064;