5-112827157-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BA1BP4

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

Publications

100 publications found

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 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

APC links:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
APC	NM_000038.6 link	c.1458T>C	p.Tyr486Tyr	synonymous_variant	Exon 12 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 link	c.1458T>C	p.Tyr486Tyr	synonymous_variant	Exon 12 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1 link	n.-58T>C		upstream_gene_variant		3		ENSP00000454861.1

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

GnomAD2 exomes

AF:

0.584

AC:

146698

AN:

251038

AF XY:

0.588

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 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

African (AFR)

AF:

0.189

AC:

6320

AN:

33450

American (AMR)

AF:

0.690

AC:

30819

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.564

AC:

14731

AN:

26116

East Asian (EAS)

AF:

0.713

AC:

28248

AN:

39642

South Asian (SAS)

AF:

0.638

AC:

55060

AN:

86240

European-Finnish (FIN)

AF:

0.517

AC:

27573

AN:

53366

Middle Eastern (MID)

AF:

0.553

AC:

3183

AN:

5760

European-Non Finnish (NFE)

AF:

0.591

AC:

656712

AN:

1111288

Other (OTH)

AF:

0.573

AC:

34556

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

18439

36878

55316

73755

92194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17976

35952

53928

71904

89880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.482

AC:

73275

AN:

152042

Hom.:

20030

Cov.:

AF XY:

0.485

AC XY:

36041

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.206

AC:

8558

AN:

41488

American (AMR)

AF:

0.623

AC:

9515

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

1905

AN:

3466

East Asian (EAS)

AF:

0.671

AC:

3470

AN:

5172

South Asian (SAS)

AF:

0.646

AC:

3116

AN:

4822

European-Finnish (FIN)

AF:

0.481

AC:

5067

AN:

10544

Middle Eastern (MID)

AF:

0.585

AC:

172

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39818

AN:

67956

Other (OTH)

AF:

0.512

AC:

1079

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1724

3448

5171

6895

8619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.528

Hom.:

20633

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

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:4

Oct 24, 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. -

Dec 09, 2019

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Mar 18, 2016

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2021

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial adenomatous polyposis 1

Benign:3

Feb 19, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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). -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30272267) -

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 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. -

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

Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

APC-Associated Polyposis Disorders

Benign:1

Mar 06, 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. -

Familial colorectal cancer

Other:1

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.1

(source)

DANN

Benign

0.78

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over