5-112815564-C-T

Position:

• chr5-112815564-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.904C>T​(p.Arg302Ter) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R302R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:1
• Conservation: PhyloP100: 4.67

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 5-112815564-C-T is Pathogenic according to our data. Variant chr5-112815564-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112815564-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.904C>T	p.Arg302Ter	stop_gained	9/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.904C>T	p.Arg302Ter	stop_gained	9/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 23, 2023	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 27, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 09, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change creates a premature translational stop signal (p.Arg302*) 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, Gardner syndrome, and colorectal cancer (PMID: 1651563, 11317365, 16317745, 20685668, 23159591, 23561487). ClinVar contains an entry for this variant (Variation ID: 798). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 27, 2017	This nonsense variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with familial adenomatous polyposis (FAP) and colorectal cancer in the published literature (PMIDs: 23561487 (2013), 23159591 (2013), and 1651563 (1991)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 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 at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 16317745, 25525159, 16134147, 20223039, 23757202, 1651563, 23561487, 8187091, 11317365, 23159591, 20685668, 12007223, 25801821, 15857185, 26917275, 20924072, 8162022, 26845104, 28127413, 26900293, 27623068, 28944238, 30897307, 32170310, 32603656, 31283021, 31942411, 31588418, 34600484, 30852976) -

Familial multiple polyposis syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2019	Variant summary: APC c.904C>T (p.Arg302X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1690C>T, p.Arg564X; c.2161_2170delGGAAGTGCTG, p.Gly721fsX3; c.3340C>T, p.Arg1114X). The variant was absent in 251112 control chromosomes (gnomAD). The variant, c.904C>T, has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Friedl_2005, Rivera_2010, Lin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified 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	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 9 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2023	The p.R302* pathogenic mutation (also known as c.904C>T), located in coding exon 8 of the APC gene, results from a C to T substitution at nucleotide position 904. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has previously been reported in multiple individuals with attenuated or classic familial adenomatous polyposis (FAP) (Nishisho I et al. Science. 1991 Aug;253:665-9; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J Mol Diagn. 2013 Jan;15(1):31-43; Torrezan GT et al. Orphanet J Rare Dis. 2013 Apr;8:54). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. -

Colorectal cancer, susceptibility to Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Nov 20, 2015

- -

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 28, 2023

This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 8162022, 20924072, 15857185, 20223039, 23561487, 31942411, 30897307). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -

Gardner syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 30, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.93, 0.96
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs137854568; hg19: chr5-112151261; COSMIC: COSV57324169;