rs386833391

chr5-112839053-TGAA-Tchr5-112839053-TGAA-TGAAGAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000038.6(APC):c.3468_3470del(p.Glu1157del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,614,062 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (5 hom.)
• Consequence: APC NM_000038.6 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:24
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-112839053-TGAA-T is Benign according to our data. Variant chr5-112839053-TGAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 41527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839053-TGAA-T is described in Lovd as [Pathogenic]. Variant chr5-112839053-TGAA-T is described in Lovd as [Likely_benign]. Variant chr5-112839053-TGAA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00393 (599/152262) while in subpopulation AFR AF= 0.0138 (574/41558). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 602 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.3468_3470del	p.Glu1157del	inframe_deletion	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.3468_3470del	p.Glu1157del	inframe_deletion	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 602 AN: 152144 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 250976 Hom.: 1 AF XY: 0.000818 AC XY: 111 AN XY: 135644

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000506 AC: 740 AN: 1461800 Hom.: 5 AF XY: 0.000435 AC XY: 316 AN XY: 727200

Gnomad4 AFR exome AF: 0.0150

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152262 Hom.: 6 Cov.: 32 AF XY: 0.00382 AC XY: 284 AN XY: 74434

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.00444

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:24

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2018	This variant is associated with the following publications: (PMID: 22703879, 21488257, 24599579, 27153395, 24345752, 24113346, 29367705) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 05, 2016	Variant summary: The APC c.3468_3470delAGA (p.Glu1157del) variant causes deletion of a Glutamic acid in a run of 4 repetitive Glutamic acids. This variant was found in 148/121852 control chromosomes (1 homozygote), predominantly observed in the African subpopulation at a frequency of 0.0130777 (133/10170). This frequency is about 183 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in patients with familial adenomatous polyposis including co-occurrences with other potentially pathogenic variants (Grandval_2014), supporting for the benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely benign/benign. Taken together, this variant is classified as Benign. -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2016	- -

Familial adenomatous polyposis 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 02, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Pathway Genomics	Jul 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 20, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 16, 2023	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 11, 2020	- -

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

Nov 30, 2015

- -

APC-Associated Polyposis Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Classic or attenuated familial adenomatous polyposis Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

actually g.112174759_112174761del, c.3468_3470del, p.E1157del was c.3460_3462del, p.1154_1154del -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs386833391; hg19: chr5-112174750;