5-112819274-C-T

Position:

chr5-112819274-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7BS1BS2BP4

This summary comes from the ClinGen Evidence Repository: The c.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (≥ 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (≥ 0.00001) for BS1. 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: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA026898/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.329

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.

BS1

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

BS2

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.1242C>T	p.Arg414Arg	synonymous_variant	10/16	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.1242C>T	p.Arg414Arg	synonymous_variant	10/16	5	NM_000038.6	ENSP00000257430.4		P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250574

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135378

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461760

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (more than 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.00001) for BS1. 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: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 05, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2018	This alteration is classified as likely 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:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2019	This variant is associated with the following publications: (PMID: 21901162, 20685668) -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant not near splice site. Reported in APC mutation spectrum paper. -

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

Dec 15, 2021

- -

Classic or attenuated familial adenomatous polyposis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

7.9

DANN

Benign

0.60

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