Variant rs730882135 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000038.6(APC):c.3149del(p.Ala1050GlufsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000124 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APC
NM_000038.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 3.85

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 190 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-112838742-GC-G is Pathogenic according to our data. Variant chr5-112838742-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 183078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838742-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.3149del	p.Ala1050GlufsTer6	frameshift_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.3149del	p.Ala1050GlufsTer6	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 17, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	This sequence change creates a premature translational stop signal (p.Ala1050Glufs6) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1794 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 11247896, 23460355, 25590978). ClinVar contains an entry for this variant (Variation ID: 183078). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Familial multiple polyposis syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2023	Variant summary: APC c.3149delC (p.Ala1050GlufsX6) results in a premature termination codon, and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250600 control chromosomes (gnomAD). c.3149delC has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (FAP), including those who also have a positive family history of FAP and/or colorectal cancer (e.g. Friedl_2001, Cruz-Correa_2013, Inra_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23460355, 11247896, 20223039, 25590978). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2020	proposed classification - variant undergoing re-assessment, contact laboratory -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2017	- -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

APC NM_000038.5 exon 15 p.Ala1050Glufs*6 (c.3149del): This variant has been reported in the literature in several individuals with familial adenomatous polyposis (FAP) (Freidl 2001 PMID:11247895, Friedl 2005 PMID:20223039, Cruz-Correa 2013 PMID:23460355, Inra 2015 PMID:25590978). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:183078). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 6 amino acids downstream from this location. This variant occurs within the last exon of the gene and therefore may escape nonsense medicated decay. However, this variant still leads to a loss >50% of the protein. Additionally, several other truncating variants downstream of this one have been reported in ClinVar as pathogenic. Of note, this variant affects the carboxyl-terminal of the protein, which is thought to be important for microtubule interaction and EB1 protein binding (Wen 2004 PMID:15311282, Moseley 2007 PMID:17293347). In summary, this variant is classified as pathogenic based on the data above. -

APC-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The APC c.3149delC variant is predicted to result in a frameshift and premature protein termination (p.Ala1050Glufs*6). This variant has been reported in individuals and/or families with adenomatous polyposis coli and/or colorectal cancer (Table 2, Friedl et al. 2001. PubMed ID: 11247896; Table S1, Friedl et al. 2005. PubMed ID: 20223039; Table 2, Cruz-Correa et al. 2013. PubMed ID: 23460355; Table S5, Inra et al. 2015. PubMed ID: 25590978). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183078/). This variant resides within the final exon of this gene and it is unclear if the resulting mRNA would undergo nonsense mediated decay: However, downstream truncating variants of this variant are reported to be pathogenic (e.g. Brensinger et al. 1998. PubMed ID: 9824584). Frameshift variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The c.3149delC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 3149, causing a translational frameshift with a predicted alternate stop codon (p.A1050Efs*6). This mutation hsa been detected in multiple individuals with Familial Adenomatous Polyposis (FAP) (Friedl W et al. Gut. 2001 Apr;48:515-21; Friedl W and Aretz S. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Steinhagen E et al. Clin Colorectal Cancer. 2012 Dec;11:304-8; Cruz-Correa M et al. Fam. Cancer. 2013 Sep;12:555-62; Inra JA et al. Genet. Med. 2015 Oct;17:815-21; Casellas-Cabrera N et al. Fam. Cancer. 2016 Apr;15:267-74). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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