chr5-112840632-C-T

Variant names:

• chr5-112840632-C-T
• rs754122018
• NM_000038.6:c.5038C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000038.6(APC):c.5038C>T (p.Gln1680Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met; Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10578390/MONDO:0021056/089

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: APC NM_000038.6 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.865
• Publications: 5 publications found

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]

APC Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.5038C>T	p.Gln1680*	stop_gained	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.5038C>T	p.Gln1680*	stop_gained	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+11660C>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 63

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

May 12, 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. -

Feb 06, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 19, 2025

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000038.6(APC):c.5038C>T (p.Gln1680Ter) variant in APC is a nonsense variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant has been reported in 1 proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PS4 not met; Ambry Genetics). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP: criteria PVS1 and PM2_Supporting applied (VCEP specifications version v2.1.0; date of approval 11/24/2023). -

Familial multiple polyposis syndrome Pathogenic:1

Sep 14, 2020

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.5038C>T (p.Gln1680X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. The variant was absent in 250054 control chromosomes (gnomAD). To our knowledge, no occurrence of c.5038C>T in individuals affected with Familial Adenomatous Polyposis has been reported. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Otsuka_2003). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Aug 02, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1680* pathogenic mutation (also known as c.5038C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 5038. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This variant has been observed in at least one individual with a personal and/or family history that is consistent with APC-associated polyposis conditions (Ambry internal data). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.50	D
PhyloP100		0.86
Vest4		0.96
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs754122018; hg19: chr5-112176329; COSMIC: COSV57384294;