5-112839326-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):​c.3732A>G​(p.Gln1244Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,316 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 30 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 27 hom. )

Consequence

APC
NM_000038.6 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.841
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 5-112839326-A-G is Benign according to our data. Variant chr5-112839326-A-G is described in ClinVar as [Benign]. Clinvar id is 183767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839326-A-G is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=0.841 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0109 (1657/152306) while in subpopulation AFR AF= 0.0375 (1558/41566). AF 95% confidence interval is 0.0359. There are 30 homozygotes in gnomad4. There are 801 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1657 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.3732A>G p.Gln1244Gln synonymous_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.3732A>G p.Gln1244Gln synonymous_variant Exon 16 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+10354A>G intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.0108
AC:
1651
AN:
152188
Hom.:
30
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0374
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00471
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:
0.0000588
Gnomad OTH
AF:
0.0110
GnomAD3 exomes
AF:
0.00304
AC:
759
AN:
249614
Hom.:
14
AF XY:
0.00224
AC XY:
303
AN XY:
135044
show subpopulations
Gnomad AFR exome
AF:
0.0381
Gnomad AMR exome
AF:
0.00349
Gnomad ASJ exome
AF:
0.0000999
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000655
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000978
Gnomad OTH exome
AF:
0.00148
GnomAD4 exome
AF:
0.00103
AC:
1511
AN:
1461010
Hom.:
27
Cov.:
33
AF XY:
0.000922
AC XY:
670
AN XY:
726742
show subpopulations
Gnomad4 AFR exome
AF:
0.0337
Gnomad4 AMR exome
AF:
0.00352
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000928
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000531
Gnomad4 OTH exome
AF:
0.00255
GnomAD4 genome
AF:
0.0109
AC:
1657
AN:
152306
Hom.:
30
Cov.:
32
AF XY:
0.0108
AC XY:
801
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0375
Gnomad4 AMR
AF:
0.00471
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.0109
Alfa
AF:
0.00429
Hom.:
8
Bravo
AF:
0.0121
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 15, 2018
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

The APC p.Gln1244Gln variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant was identified in the dbSNP (ID: rs74380081) “with benign allele”, the ClinVar database (classified as “benign” by Ambry Genetics), the Clinvitae database (classified as a “variant of unknown significance by Emory Genetics), and the UMD (3X, classified as “likely neutral”). In the UMD database, the variant was identified with a co-occurring pathogenic APC variant (c.4666delA (p.Thr1556LeufsX9)), increasing the likelihood that the p.Gln1244Gln variant does not have clinical significance. In addition, the variant was identified in several populations at polymorphic allelic frequencies: 1000 Genomes Project (frequency: 0.014), the African population in the Exome Aggregation Consortium (ExAC) database (frequency: 0.038), and the African American cohort of the Exome Variant Server ESP Project (frequency: 0.036). The variant was not identified in the literature, nor was it identified in any of the following databases: InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, GeneInsight COGR database, COSMIC. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a potential cryptic 3’ (splice donor) site; however, this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Jan 30, 2017
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4
Mar 18, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 05, 2018
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 08, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 14, 2014
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. -

Familial adenomatous polyposis 1 Benign:3
Mar 22, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

APC-Associated Polyposis Disorders Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1
Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
2.7
DANN
Benign
0.81

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: rs74380081; hg19: chr5-112175023; COSMIC: COSV99964296; COSMIC: COSV99964296; API