5-112827157-T-C

Position:

chr5-112827157-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). 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, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005169/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.48 ( 20030 hom., cov: 32)

Exomes 𝑓: 0.59 ( 255569 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:22O:1

Conservation

PhyloP100: 1.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1458T>C	p.Tyr486=	synonymous_variant	12/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1458T>C	p.Tyr486=	synonymous_variant	12/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.482

AC:

73262

AN:

151924

Hom.:

20034

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.630

Gnomad AMR

AF:

0.623

Gnomad ASJ

AF:

0.550

Gnomad EAS

AF:

0.672

Gnomad SAS

AF:

0.646

Gnomad FIN

AF:

0.481

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.515

GnomAD3 exomes

AF:

0.584

AC:

146698

AN:

251038

Hom.:

44737

AF XY:

0.588

AC XY:

79822

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.196

Gnomad AMR exome

AF:

0.698

Gnomad ASJ exome

AF:

0.563

Gnomad EAS exome

AF:

0.673

Gnomad SAS exome

AF:

0.639

Gnomad FIN exome

AF:

0.506

Gnomad NFE exome

AF:

0.592

Gnomad OTH exome

AF:

0.607

GnomAD4 exome

AF:

0.587

AC:

857202

AN:

1460910

Hom.:

255569

Cov.:

AF XY:

0.589

AC XY:

428012

AN XY:

726798

show subpopulations

Gnomad4 AFR exome

AF:

0.189

Gnomad4 AMR exome

AF:

0.690

Gnomad4 ASJ exome

AF:

0.564

Gnomad4 EAS exome

AF:

0.713

Gnomad4 SAS exome

AF:

0.638

Gnomad4 FIN exome

AF:

0.517

Gnomad4 NFE exome

AF:

0.591

Gnomad4 OTH exome

AF:

0.573

GnomAD4 genome

AF:

0.482

AC:

73275

AN:

152042

Hom.:

20030

Cov.:

AF XY:

0.485

AC XY:

36041

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.623

Gnomad4 ASJ

AF:

0.550

Gnomad4 EAS

AF:

0.671

Gnomad4 SAS

AF:

0.646

Gnomad4 FIN

AF:

0.481

Gnomad4 NFE

AF:

0.586

Gnomad4 OTH

AF:

0.512

Alfa

AF:

0.538

Hom.:

15708

Bravo

AF:

0.483

Asia WGS

AF:

0.600

AC:

2085

AN:

3478

EpiCase

AF:

0.584

EpiControl

AF:

0.587

ClinVar

Significance: Benign

Submissions summary: Benign:22Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hereditary cancer-predisposing syndrome

Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2014	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. -

Familial adenomatous polyposis 1

Benign:3

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 19, 2023	The c.1458T>C (p.Tyr486=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency (non-cancer) in gnomAD v2.1.1 is 69.75% in Latino/Admixed American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). 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, BP4, BP7 (VCEP specifications Version 1.0, date of approval: 12/12/2022). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30272267) -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

Neoplasm of stomach;C0699790:Carcinoma of colon;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.1458T>C, p.Tyr486Tyr silent variant, located in exon 12 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs_id:rs2229992) with a minor allele frequency of 0.46. Based on the above information, this is a likely benign variant. -

Familial colorectal cancer

Other:1

other, no assertion criteria provided

literature only

Systems Biology Platform Zhejiang California International NanoSystems Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.1

DANN

Benign

0.78

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