5-112842303-C-T

Position:

• chr5-112842303-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.6709C>T​(p.Arg2237Ter) 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 1,461,514 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R2237R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.42

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 91 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112842303-C-T is Pathogenic according to our data. Variant chr5-112842303-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 187612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112842303-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.6709C>T	p.Arg2237Ter	stop_gained	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.6709C>T	p.Arg2237Ter	stop_gained	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461514 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 16, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Arg2237*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 607 amino acid(s) of the APC protein. This variant is present in population databases (rs768922431, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 187612). 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. -

Familial multiple polyposis syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2019	The p.Arg2237X variant in APC has been previously reported in 1 individual with attenuated familial adenomatous polyposis (FAP) (Kerr 2013) and has been reported in ClinVar (Variation ID#187612). This variant has been identified in 1/22278 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 2237. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Truncating variants in the last exon of APC, including multiple variants downstream of this variant, have been reported in individuals with FAP. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg2237X variant is classified as likely pathogenic for familial adenomatous polyposis in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1_Strong, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jul 05, 2018	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 15, 2022	This variant changes 1 nucleotide in exon 16 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 an individual affected with attenuated familial adenomatous polyposis (PMID: 23159591) and in individuals affected with colorectal cancer (PMID: 35205366; Color internal data). This variant has been identified in 1/245798 chromosomes 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	Jul 12, 2022	The p.R2237* pathogenic mutation (also known as c.6709C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 6709. This changes the amino acid from an arginine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 617 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This mutation was previously reported in an individual with attenuated polyposis (Kerr SE et al. J Mol Diagn. 2013 Jan; 15(1):31-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2022

Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30720243, 31447099, 24951259, 33941878, 23159591, 34427956, 35205366) -

Neoplasm Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D;D
Vest4		0.98
GERP RS		5.1

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: rs768922431; hg19: chr5-112178000; COSMIC: COSV57327470; COSMIC: COSV57327470;