Submissions for variant NM_000038.6(APC):c.74_75del (p.Gln25fs)

dbSNP: rs1554067124

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004561612	SCV000647711	pathogenic	Familial adenomatous polyposis 1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln25Argfs*5) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). 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: 23159591). ClinVar contains an entry for this variant (Variation ID: 470090). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657188	SCV000778910	pathogenic	not provided	2018-05-07	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in APC is denoted c.74_75delAA at the cDNA level and p.Gln25ArgfsX5 (Q25RfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CGAC[delAA]GAGC. The deletion causes a frameshift which changes a Glutamine to an Arginine at codon 25, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.74_75delAA has been observed in at least one individual undergoing genetic testing due to a clinical presentation suggestive of familial adenomatous polyposis (Kerr 2013). We consider this variant to be pathogenic.
Ambry Genetics	RCV002384184	SCV002671228	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	clinical testing	The c.74_75delAA pathogenic mutation, located in coding exon 1 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 74 to 75, causing a translational frameshift with a predicted alternate stop codon (p.Q25Rfs*5). In a large (n=1,591) series of patients referred for APC testing, this alteration was detected in one individual. (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. However, alterations that result in premature termination in coding exon 1 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised.
Fulgent Genetics, Fulgent Genetics	RCV002497160	SCV002813950	pathogenic	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-04-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004561612	SCV004045669	pathogenic	Familial adenomatous polyposis 1	2023-04-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.