5-112775612-TAAA-TAA

Position:

• chr5-112775612-TAAA-TAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.423-4del variant in APC is an intronic variant which results in the deletion of adenine at position -4 of intron 4. The highest allele frequency is 5.48% in gnomAD v3.1.2, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold for BA1 (≥ 0.1%). RNA assays showed no splicing mutation, indicating that this variant does not impact protein function (BS3_Supporting; PMID22447671). Finally, the results from ≥2 in silico splicing predictors support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BS3_Supporting, BP4. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV181781/MONDO:0021056/089

• Frequency:
  • Genomes: 𝑓 0.018 (70 hom., cov: 32)
  • Exomes 𝑓: 0.18 (13 hom.)
• Consequence: APC NM_000038.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:18
• Conservation: PhyloP100: -0.937

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 Benign. Variant got -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.423-4del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.423-4del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2623 AN: 143400 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

Gnomad ASJ AF: 0.00418

Gnomad EAS AF: 0.00239

Gnomad SAS AF: 0.00984

Gnomad FIN AF: 0.00738

Gnomad MID AF: 0.00676

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.0205

GnomAD4 exome AF: 0.182 AC: 155333 AN: 853448 Hom.: 13 Cov.: 0 AF XY: 0.185 AC XY: 78147 AN XY: 422492

Gnomad4 AFR exome AF: 0.232

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.217

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.0183 AC: 2631 AN: 143460 Hom.: 70 Cov.: 32 AF XY: 0.0183 AC XY: 1276 AN XY: 69562

Gnomad4 AFR AF: 0.0549

Gnomad4 AMR AF: 0.00725

Gnomad4 ASJ AF: 0.00418

Gnomad4 EAS AF: 0.00240

Gnomad4 SAS AF: 0.00987

Gnomad4 FIN AF: 0.00738

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.0208

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:18

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2014	The variant is found in COLO-HEREDIC panel(s). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 13, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial adenomatous polyposis 1 Benign:3

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 18, 2023	The c.423-4del variant in APC is an intronic variant which results in the deletion of adenine at position -4 of intron 4. The highest allele frequency is 5.48% in gnomAD v3.1.2, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold for BA1 (0.1%). RNA assays showed no splicing mutation, indicating that this variant does not impact protein function (BS3_Supporting; PMID22447671). Finally, the results from more than or equal to 2 in silico splicing predictors support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BS3_Supporting, BP4. (VCEP specifications version 1; date of approval: 12/12/2022). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 23, 2024	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 13, 2022

- -

APC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs730881230; hg19: chr5-112111309;