5-112842795-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):c.7201C>T(p.Leu2401Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,536 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 8 hom., cov: 32)

Exomes 𝑓: 0.013 ( 166 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:25

Conservation

PhyloP100: 3.42

Variant links:

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 links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 5-112842795-C-T is Benign according to our data. Variant chr5-112842795-C-T is described in ClinVar as [Benign]. Clinvar id is 42249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112842795-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=3.41 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0111 (1696/152246) while in subpopulation AMR AF= 0.017 (260/15296). AF 95% confidence interval is 0.0153. There are 8 homozygotes in gnomad4. There are 816 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1696 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.7201C>T	p.Leu2401Leu	synonymous_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.7201C>T	p.Leu2401Leu	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 link	n.228+13823C>T		intron_variant	Intron 3 of 7	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1696

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00860

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0170

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0135

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0101

AC:

2514

AN:

250140

Hom.:

AF XY:

0.0100

AC XY:

1355

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00808

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0162

GnomAD4 exome

AF:

0.0128

AC:

18702

AN:

1461290

Hom.:

166

Cov.:

AF XY:

0.0125

AC XY:

9072

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00899

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0229

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0111

AC:

1696

AN:

152246

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

816

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00862

Gnomad4 AMR

AF:

0.0170

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00189

Gnomad4 NFE

AF:

0.0135

Gnomad4 OTH

AF:

0.0138

Alfa

AF:

0.0138

Hom.:

Bravo

AF:

0.0124

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:25

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu2401Leu in exon 15 of APC: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.3% (92/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; rs2229994). -

Aug 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 16, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:5

May 11, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 27, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 22, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BP4, BP7, BS1, BS2 -

Oct 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1

Benign:3

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Leu2401Leu variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, and is listed in the dbSNP database as coming from a "clinical source" (ID#: rs2229994) with an average heterozygosity of 0.022+/-0.103, therefore increasing the likelihood of this variant to be benign. It has been identified in our laboratory in one among the 973 individuals who have undergone APC testing. Additionally, it has been identified twice in the literature, in 2/258 (0.007% frequency) proband chromosomes and 1/1052 (0.001 frequency) control chromosomes where it was classified as a polymorhism (Hadjisavvas_2006_16650078, Zhou_2004_15122587). In summary, based on the above information, the p.Leu2401Leu variant is classified as predicted benign. -

APC-Associated Polyposis Disorders

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Classic or attenuated familial adenomatous polyposis

Benign:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.6

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over