Submissions for variant NM_000038.6(APC):c.350C>A (p.Ser117Ter)

dbSNP: rs1064793535

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482015	SCV000566355	pathogenic	not provided	2017-10-18	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted APC c.350C>A at the cDNA level and p.Ser117Ter (S117X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with attenuated Familial Adenomatous Polyposis (Kerr 2013) and is considered pathogenic.
Ambry Genetics	RCV000561431	SCV000675927	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.S117* pathogenic mutation (also known as c.350C>A), located in coding exon 3 of the APC gene, results from a C to A substitution at nucleotide position 350. This changes the amino acid from a serine to a stop codon within coding exon 3. This mutation has been detected in multiple individuals with familial adenomatous polyposis (FAP) (Wu G et al. Genet. Test., 2001;5:281-90; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43; Gutierrez Sanchez LH et al. Gastrointest Endosc, 2018 Mar;87:648-656.e3). In addition to the clinical data presented in the literature, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525784	SCV000768277	pathogenic	Familial adenomatous polyposis 1	2024-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser117*) 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 APC-related disease (PMID: 11960572, 23159591). ClinVar contains an entry for this variant (Variation ID: 418932). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824795	SCV002074167	pathogenic	Familial multiple polyposis syndrome	2022-01-10	criteria provided, single submitter	clinical testing	Variant summary: APC c.350C>A (p.Ser117X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251476 control chromosomes (gnomAD). c.350C>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (examples: Wu_2001, Kerr_2013 and Findlen_2021). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV002525784	SCV004045531	pathogenic	Familial adenomatous polyposis 1	2023-04-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV004722817	SCV005335909	pathogenic	APC-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The APC c.350C>A variant is predicted to result in premature protein termination (p.Ser117*). This variant has been reported in an individual with classic familial adenomatous polyposis (FAP) (Table 1. Findlen et al. 2021. PubMed ID: 33788735) and in an individual with attenuated FAP (Table 5. Kerr et al. 2012. PubMed ID: 23159591). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418932/). Nonsense variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic.