rs1060503326

Positions:

• chr5-112839169-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):​c.3577_3578delCA​(p.Gln1193fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.54

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]

ENSG00000258864 (HGNC:):

ACMG classification

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 142 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839169-AAC-A is Pathogenic according to our data. Variant chr5-112839169-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 411475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839169-AAC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6	c.3577_3578delCA	p.Gln1193fs	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	c.3577_3578delCA	p.Gln1193fs	frameshift_variant	16/16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10199_228+10200delCA		intron_variant		3		ENSP00000454861.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2025	This sequence change creates a premature translational stop signal (p.Gln1193Valfs*14) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1651 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 (FAP) (PMID: 1843350, 7746201, 8730280, 9067764, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 411475). 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.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, internal data). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 09, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2019

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Dobbie 1996, De Rosa 2003, Kanter-Smoler 2008); This variant is associated with the following publications: (PMID: 31269945, 8730280, 18433509, 20685668, 20223039, 14961559, 23159591, 9067764, 7746201) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2022

The c.3577_3578delCA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides between nucleotide positions 3577 and 3578, causing a translational frameshift with a predicted alternate stop codon (p.Q1193Vfs*14). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1651 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration has been detected in individuals with personal and family histories of familial adenomatous polyposis (FAP) (Kerr SE et al. J Mol Diagn 2013;15(1):31-43; Friedl W et al. Hered Cancer Clin Pract 2005;3(3):95-114; Dobbie Z et al. J. Med. Genet. 1996;33(4):274-80; Scarano MI et al. Hum. Mutat. 1997;9(2):191-3; Gerdehsang PS et al. Intl. Journal Hum. Genet. 2017;14(4):145-150). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

APC-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2024

The APC c.3577_3578delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln1193Valfs*14). This variant was reported in individuals with adenomatous polyposis coli (for example, Lagarde et al. 2010. PubMed ID: 20685668; reported as somatic mosaicism in Kim B et al 2019. PubMed ID: 31269945; Dobbie Z et al 1996. PubMed ID: 8730280; Kerr SE et al 2012. PubMed ID: 23159591). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is also classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411475/). Based on above information, this variant is interpreted as pathogenic. -

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: rs1060503326; hg19: chr5-112174866;