chr5-112828864-G-A

Position:

chr5-112828864-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.1635G>A (p.Ala545=) variant is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.82 (15756 in 19198 alleles) in the East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.001) 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, and BP7. (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005411/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.60 ( 27988 hom., cov: 33)

Exomes 𝑓: 0.63 ( 289133 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:19O:1

Conservation

PhyloP100: 1.61

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:

APC (HGNC:):

APC links:

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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.1635G>A	p.Ala545Ala	synonymous_variant	14/16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1635G>A	p.Ala545Ala	synonymous_variant	14/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.120G>A		non_coding_transcript_exon_variant	3/8	3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.601

AC:

91390

AN:

151970

Hom.:

27971

Cov.:

show subpopulations

Gnomad AFR

AF:

0.534

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.669

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.819

Gnomad SAS

AF:

0.732

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.613

Gnomad OTH

AF:

0.613

GnomAD3 exomes

AF:

0.649

AC:

162952

AN:

250988

Hom.:

53916

AF XY:

0.649

AC XY:

88028

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.532

Gnomad AMR exome

AF:

0.733

Gnomad ASJ exome

AF:

0.581

Gnomad EAS exome

AF:

0.822

Gnomad SAS exome

AF:

0.714

Gnomad FIN exome

AF:

0.559

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.649

GnomAD4 exome

AF:

0.628

AC:

911919

AN:

1453172

Hom.:

289133

Cov.:

AF XY:

0.630

AC XY:

455355

AN XY:

723316

show subpopulations

Gnomad4 AFR exome

AF:

0.518

Gnomad4 AMR exome

AF:

0.726

Gnomad4 ASJ exome

AF:

0.581

Gnomad4 EAS exome

AF:

0.840

Gnomad4 SAS exome

AF:

0.710

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.616

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.601

AC:

91459

AN:

152088

Hom.:

27988

Cov.:

AF XY:

0.603

AC XY:

44816

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.534

Gnomad4 AMR

AF:

0.669

Gnomad4 ASJ

AF:

0.566

Gnomad4 EAS

AF:

0.819

Gnomad4 SAS

AF:

0.732

Gnomad4 FIN

AF:

0.536

Gnomad4 NFE

AF:

0.613

Gnomad4 OTH

AF:

0.610

Alfa

AF:

0.610

Hom.:

35610

Bravo

AF:

0.610

Asia WGS

AF:

0.754

AC:

2619

AN:

3476

EpiCase

AF:

0.610

EpiControl

AF:

0.612

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2008	- -

Familial adenomatous polyposis 1

Benign:4

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 19, 2023	The c.1635G>A (p.Ala545=) variant is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.82 (15756 in 19198 alleles) in the East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.001) 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, and BP7. (VCEP specifications version 1; date of approval: 12/12/2022). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2016	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 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. -
Benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 21, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The c.1635G>A, p.Ala545Ala silent variant, located in exon 14 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is 9 bp away from the nearest splice junction, is listed in dbSNP (rs_id: rs351771) with a heterozygosity frequency of 0.479+/-0.099. Based on the above information, this is a likely benign variant. -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

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

-0.32

CADD

Benign

DANN

Benign

0.76

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