5-112819272-C-T

Position:

chr5-112819272-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BS2BA1BP1BP2

This summary comes from the ClinGen Evidence Repository: The c.1240C>T variant in APC is a missense variant predicted to cause the substitution of arginine by cysteine at amino acid 414 (p.Arg414Cys). This variant has been observed in heterozygous state in ≥ 1000 healthy unrelated adult individuals worth ≥ 10 healthy individual points in total (BS2; Invitae, Ambry, and GeneDX internal data). It has been observed in trans with a variant classified as Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) in an individual with FAP (BP2). The highest allele frequency of this variant is 0.001835 in European (Finnish) population, which is higher than the HCCP VCEP threshold (≥ 0.001) for BA1. Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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, BS2, BP1 and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA004103/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00072 ( 1 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel P:1U:3B:23O:1

Conservation

PhyloP100: 6.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP1

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

BP2

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

BS2

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.1240C>T	p.Arg414Cys	missense_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.1240C>T	p.Arg414Cys	missense_variant	10/16	5	NM_000038.6	ENSP00000257430.4		P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000667

AC:

167

AN:

250544

Hom.:

AF XY:

0.000643

AC XY:

AN XY:

135362

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000983

GnomAD4 exome

AF:

0.000718

AC:

1049

AN:

1461738

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

490

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00184

Gnomad4 NFE exome

AF:

0.000816

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000492

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000564

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000741

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000865

AC:

105

EpiCase

AF:

0.000382

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:3Benign:23Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:8

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	This variant is associated with the following publications: (PMID: 20223039, 22703879, 19822006, 29936255, 25637381, 21859464, 1651563, 24728327, 1316610, 11317365, 18199528, 20685668, 25142776, 22000517, 24790607, 14633595, 26332594, 27621404, 27930734, 28135136, 27435373, 29549174) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	APC: BS1:Supporting, BS3:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	Variant summary: The APC c.1240C>T (p.Arg414Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. However, a functional study found that this variant maintained inhibitory activity on the transcription mediated by the beta-catenin/TCF4 complex, as did wild-type APC. The variant of interest has been found in a large, broad control population, ExAC in 105/120892 control chromosomes at a frequency of 0.0008685, which is approximately 12 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this variant is likely a benign polymorphism. This variant was found in multiple studies in FAP patients (van der Klift_PMS2_Hum Mutat_2016, Azzopardi_CancerRsrch_2008) but one functional study and the high frequency in population suggests a benign effect. In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Familial adenomatous polyposis 1

Uncertain:2Benign:5

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 18, 2023	The c.1240C>T variant in APC is a missense variant predicted to cause the substitution of arginine by cysteine at amino acid 414 (p.Arg414Cys). This variant has been observed in heterozygous state in more than 1000 healthy unrelated adult individuals worth more than 10 healthy individual points in total (BS2; Invitae, Ambry, and GeneDX internal data). It has been observed in trans with a variant classified as Pathogenic by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) in an individual with FAP (BP2). The highest allele frequency of this variant is 0.001835 in European (Finnish) population, which is higher than the HCCP VCEP threshold (0.001) for BA1. Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). 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, BS2, BP1 and BP2 (VCEP specifications version 1; date of approval: 12/12/2022). -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 05, 2021	The APC c.1240C>T (p.Arg414Cys) missense change has a maximum non-founder subpopulation frequency of 0.097% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112154969-C-T). This is higher than the reported incidence of APC-related familial adenomatous polyposis (BS1). It was also found to be homozygous in one individual (BS2_supporting). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but a functional assay indicated that this variant maintained inhibitor activity on the transcription mediated by the beta-catenin/TCF4 complex, similar to the wild-type (BS3_supporting). This variant has been reported in individuals with confirmed or suspected FAP and attenuated FAP (PMID: 18199528, 20223039, 24790607, 25142776, 27435373, 31285513). In one case, the patient's adenoma demonstrated that the tumor lost the allele carrying the p.R414C variant and retained only the normal allele, suggesting a benign effect (PMID: 24790607). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BS2_supporting, BS3_supporting, PP3. -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Oct 15, 2024	The missense variant NM_000038.6(APC):c.1240C>T (p.Arg414Cys) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 797 as of 2024-10-03). The variant is observed in one or more well-documented healthy adults. The p.Arg414Cys variant is observed in 40/21,606 (0.1851%) alleles from individuals of gnomAD European Finnish background in gnomAD, which is greater than expected for the disorder. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.Arg414Cys missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 414 of APC is conserved in all mammalian species. The nucleotide c.1240 in APC is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 04, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 12, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2015	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 specified

Benign:4Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Arg414Cys variant in APC has been reported in 1 individual with FAP (Azzopardi 2008 PMID: 18199528). It has also been identified in 0.18% (46/25082) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 797) where labs such as Invitae have classified this variant as benign. In vitro functional studies provide some evidence that this does not impact protein function (Yamada 2003 PMID: 14633595); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PS4_Supporting. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Gardner syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 09, 1991

- -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 07, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

.;D;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Benign

0.080

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

-0.066

MutationAssessor

Benign

2.0

.;M;M;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-7.9

D;D;D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.94, 0.88

MVP

0.94

ClinPred

0.31

GERP RS

5.9

Varity_R

0.95

gMVP

0.66

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