rs72541809

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000038.6(APC):​c.1959G>A​(p.Arg653Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,610,582 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R653R) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0055 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0041 ( 27 hom. )

Consequence

APC
NM_000038.6 splice_region, synonymous

Scores

2
Splicing: ADA: 0.003458
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27O:1

Conservation

PhyloP100: 3.35
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 -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
Variant 5-112837553-G-A is Benign according to our data. Variant chr5-112837553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 133524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112837553-G-A is described in Lovd as [Benign]. Variant chr5-112837553-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=3.36 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00548 (833/152138) while in subpopulation NFE AF= 0.00463 (315/68002). AF 95% confidence interval is 0.00421. There are 4 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 833 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.1959G>A p.Arg653Arg splice_region_variant, 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.1959G>A p.Arg653Arg splice_region_variant, synonymous_variant Exon 16 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+8581G>A intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.00547
AC:
832
AN:
152020
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000773
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00334
Gnomad ASJ
AF:
0.00144
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0398
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00463
Gnomad OTH
AF:
0.00335
GnomAD3 exomes
AF:
0.00504
AC:
1261
AN:
250358
Hom.:
12
AF XY:
0.00509
AC XY:
690
AN XY:
135458
show subpopulations
Gnomad AFR exome
AF:
0.000745
Gnomad AMR exome
AF:
0.00125
Gnomad ASJ exome
AF:
0.000497
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0318
Gnomad NFE exome
AF:
0.00427
Gnomad OTH exome
AF:
0.00525
GnomAD4 exome
AF:
0.00409
AC:
5972
AN:
1458444
Hom.:
27
Cov.:
31
AF XY:
0.00406
AC XY:
2947
AN XY:
725370
show subpopulations
Gnomad4 AFR exome
AF:
0.000748
Gnomad4 AMR exome
AF:
0.00128
Gnomad4 ASJ exome
AF:
0.000957
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0292
Gnomad4 NFE exome
AF:
0.00369
Gnomad4 OTH exome
AF:
0.00340
GnomAD4 genome
AF:
0.00548
AC:
833
AN:
152138
Hom.:
4
Cov.:
32
AF XY:
0.00707
AC XY:
526
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.000771
Gnomad4 AMR
AF:
0.00334
Gnomad4 ASJ
AF:
0.00144
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0398
Gnomad4 NFE
AF:
0.00463
Gnomad4 OTH
AF:
0.00332
Alfa
AF:
0.00377
Hom.:
4
Bravo
AF:
0.00245
EpiCase
AF:
0.00469
EpiControl
AF:
0.00415

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:27Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8Other:1
Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Feb 07, 2020
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2014
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

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

- -

-
Clinical Genetics, Academic 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: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 02, 2016
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:7
Jun 20, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The APC c.1959G>A (p.Arg653Arg) variant involves the alteration of a conserved nucleotide one nucleotide downstream from the intron-exon boundary, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. Consistent with these predictions, in vitro as well as ex vivo analysis shows that this variant does not cause abnormal splicing (Aretz_2004, Grandval_2014). This variant was found in 538/119468 control chromosomes (including 6 homozygotes), predominantly observed in the European (Finnish), subpopulation at a frequency of 0.0323708 (213/6580). This frequency is about 453 times greater than the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has also been reported in several FAP patients (Aretz_2004, Stekrova_2007, Grandval_2014, UMD); however, some patients also carried another deleterious variant in the same gene, strongly suggesting for the benign outcome. In addition, multiple clinical diagnostic laboratories and one reputable database have classified this variant as benign. Taken together, this variant is classified as Benign. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

APC: BP4, BS1, BS2 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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

- -

Mar 20, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5
Nov 22, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 10, 2017
True Health Diagnostics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 02, 2021
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Dec 12, 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. -

Mar 17, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Benign:4
Mar 08, 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. -

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

- -

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

- -

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

- -

Familial multiple polyposis syndrome Benign:1
Oct 19, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
13
DANN
Benign
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0035
dbscSNV1_RF
Benign
0.26
SpliceAI score (max)
0.040
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: rs72541809; hg19: chr5-112173250; COSMIC: COSV104379132; API