5-112828919-C-T

Position:

• chr5-112828919-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.1690C>T​(p.Arg564Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R564R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 2.60

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112828919-C-T is Pathogenic according to our data. Variant chr5-112828919-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828919-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1690C>T	p.Arg564Ter	stop_gained	14/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1690C>T	p.Arg564Ter	stop_gained	14/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461584 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 17, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2021	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 in large population cohorts (Lek 2016); Observed in individuals with a personal and/or family history consistent with pathogenic variants in this gene including a de novo observation with confirmed parentage in a patient with polyposis (Mihalatos 2003, Aretz 2004, Friedl 2005, Papp 2015); This variant is associated with the following publications: (PMID: 12894596, 20685668, 9101302, 27087319, 26446593, 19036155, 20223039, 1324223, 25525159, 27574554, 14523376, 12581900, 8187091, 31243121, 29506128, 28179590, 8381580) -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 01, 2024	- -

Familial adenomatous polyposis 1 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg564*) 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: 1324223, 15833136, 19036155, 20223039, 20685668, 26446593). ClinVar contains an entry for this variant (Variation ID: 808). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 02, 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	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The stop gained c.1690C>T (p.Arg564Ter) variant in APC gene has been reported in heterozygous state in multiple individuals affected with adenomatous polyposis (Papp J et al. 2016; Nilbert M et al. 2008; Friedl W et al. 2005). The p.Arg564Ter variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The nucleotide change c.1690C>T in APC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates.This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Familial multiple polyposis syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 06, 2019	The p.Arg564X variant in APC has been reported in >25 individuals with FAP (Fodde 1992, Miyaki 1994, Aretz 2004, Mihalatos 2005, Friedl 2005, Lagarde 2010, and InSiGHT Colon Cancer database: http://insight-database.org/) and was absent from large population studies. This variant has also been reported by other clinical laboratories in ClinVar (Variant ID: 808). This nonsense variant leads to a premature termination codon at position 564, which is predicted to lead to a truncated or absent protein. Loss of function of the APC gene is an established disease mechanism in autosomal dominant familial adenomatous polyposis (FAP). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FAP. ACMG/AMP criteria applied: PVS1, PM2, PS4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2019	Variant summary: APC c.1690C>T (p.Arg564X) 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 246076 control chromosomes (gnomAD). c.1690C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (Friedl_2005, Aretz_2004, Olschwang_1993). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 28, 2021	The p.R564* pathogenic mutation (also known as c.1690C>T), located in coding exon 13 of the APC gene, results from a C to T substitution at nucleotide position 1690. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals diagnosed with FAP (Fodde R et al. Genomics 1992 Aug;13(4):1162-8; Friedl W and Aretz S. Hered. Cancer Clin Pract. 2005 Sep 15;3(3):95-114; Nilbert M et al. BMC Med. Genet. 2008 Nov 26;9:101; Papp J et al. Fam. Cancer 2016 Jan;15:85-97; Weiss V et al. World J. Gastrointest. Oncol. 2016 Aug;8:615-22; Tsukanov AS et al. Russian J. of Genet. 2017 Mar;53(3):369-75). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 23, 2021	This variant changes 1 nucleotide in exon 14 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: 8990002, 10077047, 12581900, 16478792, 19036155, 19444466, 19793053, 20223039, 20685668, 23159591, 26446593) or affected with colorectal cancer (PMID: 25590978). 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. -

Classic or attenuated familial adenomatous polyposis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 08, 2023

The c.1690C>T (p.Arg564*) variant in the APC gene is located on the exon 14 and is predicted to introduce a premature translation termination codon (p.Arg564*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with familial adenomatous polyposis/colorectal cancer (PMID: PMID: 19444466, 33359728, 26446593, 33279946, 19036155). Loss-of-function variants of APC are known to be pathogenic and frameshift/truncating variants located upstream and downstream to this position have been reported in individuals with familial adenomatous polyposis/colorectal cancer (PMID: 26446593, 23159591, 31591141, 33769591). The variant is reported in ClinVar as pathogenic (ID: 808). The variant is absent in the general population database (gnomAD). Therefore, the c.1690C>T (p.Arg564*) variant of APC has been classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98, 0.98
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs137854574; hg19: chr5-112164616; COSMIC: COSV57321509;