5-112819272-C-T

Position:

• chr5-112819272-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BA1 BP1 BP2 BS2

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
• Clinical Significance: Benign reviewed by expert panel P:1 U:3 B:22 O:1
• Conservation: PhyloP100: 6.04

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1240C>T	p.Arg414Cys	missense_variant	10/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1240C>T	p.Arg414Cys	missense_variant	10/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152168 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000643 AC XY: 87 AN XY: 135362

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.: 1 Cov.: 33 AF XY: 0.000674 AC XY: 490 AN XY: 727166

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: 75 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74462

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.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.000382

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:3 Benign:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:8

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	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	APC: BS1:Supporting, BS3:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 01, 2017	- -
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:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -
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. -
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). -

not specified Benign:4 Other:1

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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	-	- -

Hereditary cancer-predisposing syndrome Benign:4

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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 12, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 04, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 04, 2016	- -

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	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	-0.066	T
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.90	D
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	T
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

Other links and lift over

dbSNP: rs137854567; hg19: chr5-112154969; COSMIC: COSV57342477; COSMIC: COSV57342477;