rs72541809

Positions:

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.Arg653=) 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

Splicing: ADA: 0.003458

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]

APC links:

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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/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1959G>A	p.Arg653=	splice_region_variant, synonymous_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1959G>A	p.Arg653=	splice_region_variant, synonymous_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.00547

AC:

832

AN:

152020

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

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

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 07, 2020	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	APC: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2014	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 22, 2022	- -

Familial adenomatous polyposis 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 08, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Familial multiple polyposis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 19, 2015

- -

APC-Associated Polyposis Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over