NM_000038.6:c.4420G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BS3_SupportingBP1

This summary comes from the ClinGen Evidence Repository: The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (≥ 0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of β-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID:18199528). 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, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CV133530/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.0029 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00031 ( 2 hom. )

Consequence

APC
NM_000038.6 missense

Scores

5
13

Clinical Significance

Benign reviewed by expert panel U:1B:15O:1

Conservation

PhyloP100: 3.96
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP1
For more information check the summary or visit ClinGen Evidence Repository.
BS3
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
APCNM_000038.6 linkc.4420G>A p.Ala1474Thr missense_variant Exon 16 of 16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.4420G>A p.Ala1474Thr missense_variant Exon 16 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+11042G>A intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.00293
AC:
446
AN:
152138
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0103
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00111
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.000773
AC:
194
AN:
251084
Hom.:
1
AF XY:
0.000656
AC XY:
89
AN XY:
135684
show subpopulations
Gnomad AFR exome
AF:
0.0107
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.000313
AC:
458
AN:
1461874
Hom.:
2
Cov.:
33
AF XY:
0.000282
AC XY:
205
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0118
Gnomad4 AMR exome
AF:
0.000470
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:
0.00000270
Gnomad4 OTH exome
AF:
0.000613
GnomAD4 genome
AF:
0.00294
AC:
447
AN:
152256
Hom.:
6
Cov.:
32
AF XY:
0.00302
AC XY:
225
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0103
Gnomad4 AMR
AF:
0.00111
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000598
Hom.:
1
Bravo
AF:
0.00359
ESP6500AA
AF:
0.00999
AC:
44
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000906
AC:
110
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:15Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:4
Apr 10, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 26, 2023
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). 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, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
Jul 08, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Dec 04, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18199528, 24728327, 24055113, 24861525, 25637381, 21859464, 26332594) -

Hereditary cancer-predisposing syndrome Benign:3
Mar 21, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Jan 04, 2015
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. -

Mar 23, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2Other:1
Oct 27, 2016
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 25, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Colorectal adenoma Uncertain:1
Jun 01, 2014
CSER _CC_NCGL, University of Washington
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The APC p.Ala1474Thr variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal polyps (Azzopardi, 2008). The variant was also identified in dbSNP (ID: rs139387758 as With Uncertain significance allele), ClinVar (3x as benign, 2x as likely benign, 1x as a variant of uncertain significance), Cosmic (2x), LOVD 3.0 (1x as not classified), and UMD-LSDB (1x). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 290 of 276830 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 270 of 24026 chromosomes (freq: 0.01), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European Non-Finnish in 4 of 126384 chromosomes (freq: 0.00003), and SouthAsian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Ala1474 residue is moderately conserved in mammals, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign. -

APC-Associated Polyposis Disorders Benign:1
Nov 29, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Classic or attenuated familial adenomatous polyposis Benign:1
Feb 05, 2024
All of Us Research Program, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.41
T;T
Eigen
Benign
0.068
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.83
.;T
MetaRNN
Benign
0.0087
T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
0.46
N;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.090
N;N
REVEL
Uncertain
0.34
Sift
Benign
0.13
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0020
B;B
Vest4
0.75
MVP
0.77
ClinPred
0.025
T
GERP RS
6.2
Varity_R
0.075
gMVP
0.61

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.

Other links and lift over

dbSNP: rs139387758; hg19: chr5-112175711; COSMIC: COSV57345841; COSMIC: COSV57345841; API