Submissions for variant NM_000038.6(APC):c.32dup (p.Gln12fs)

dbSNP: rs1561444620

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002534025	SCV003836620	uncertain significance	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.32dup (p.Gln12Alafs*3) variant in APC is a duplication variant which inserts 1 nucleotide in the first coding exon of the APC gene, creating a frameshift and premature translation stop signal. Since the frameshift and the premature truncation codon occurs upstream of codon 49, PVS1 does not apply according to the APC-specific modifications of the PVS1 decision tree (PVS1 not met). The variant is not reported in gnomAD v2.1.1 (PM2_supporting). This variant has been observed in heterozygous state in 3 healthy unrelated adult individuals worth 1.5 healthy individual points in total (BS2_variable not met; Invitae and GeneDX internal data). In summary, this variant is a VUS for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PM2_Supporting (VCEP specifications version 1; date of approval 12/12/22).
Color Diagnostics, LLC DBA Color Health	RCV000772573	SCV000905753	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 of the APC gene, creating a frameshift and premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). To our knowledge, this variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV002534025	SCV000948869	pathogenic	Familial adenomatous polyposis 1	2018-09-10	criteria provided, single submitter	clinical testing	Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant has not been reported in the literature in individuals with APC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln12Alafs*3) in the APC gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000772573	SCV004053851	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The c.32dupA variant, located in coding exon 1 of the APC gene, results from a duplication of A at nucleotide position 32, causing a translational frameshift with a predicted alternate stop codon (p.Q12Afs*3). The predicted stop codon occurs in the 5’ end of theAPC gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003999974	SCV004841685	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-06	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 of the APC gene, creating a frameshift and premature translation stop signal. Alterations that cause premature truncation in the amino (N-) terminus of the APC protein have been associated with an attenuated phenotype and may have reduced penetrance and/or expressivity in comparison to classic familial adenomatous polyposis syndrome (FAP; PMID: 9585611, 11257105). To our knowledge, this variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance
GeneDx	RCV004797870	SCV005419470	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Frameshift variant in a gene for which loss-of-function is a known mechanism of disease; however, a downstream in-frame Methionine residue could serve as an alternate initiator codon which, if utilized, may result in a functional protein; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 37800450)