rs139387758

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/exons MANE Protein UniProt
APCNM_000038.6 linkuse as main transcriptc.4420G>A p.Ala1474Thr missense_variant 16/16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkuse as main transcriptc.4420G>A p.Ala1474Thr missense_variant 16/165 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkuse as main transcriptn.228+11042G>A intron_variant 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
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, reviewed by expert panelcurationClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert PanelFeb 26, 2023The 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). -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 10, 2024This 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. -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 08, 2022- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 04, 2018This variant is associated with the following publications: (PMID: 18199528, 24728327, 24055113, 24861525, 25637381, 21859464, 26332594) -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submittercurationSema4, Sema4Mar 21, 2020- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 04, 2015This 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, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 23, 2016- -
not specified Benign:2Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 25, 2017- -
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 27, 2016- -
Colorectal adenoma Uncertain:1
Uncertain significance, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
APC-Associated Polyposis Disorders Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 29, 2018This 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. -
Carcinoma of colon Benign:1
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Classic or attenuated familial adenomatous polyposis Benign:1
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -

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