Submissions for variant NM_000038.6(APC):c.1370C>A (p.Ser457Ter)

dbSNP: rs1060503333

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003743762	SCV000647170	pathogenic	Familial adenomatous polyposis 1	2021-09-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 433620). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) and an individual with concomitant congenital hypertrophy of the retinal pigment epithelium (CHRPE) (PMID: 7959691, 20223039, 20685668). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser457*) 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).
Color Diagnostics, LLC DBA Color Health	RCV001186209	SCV001352561	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 of the APC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with or suspected of having familial adenomatous polyposis (PMID: 20223039, 20685668). 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). Based on the available evidence, this variant is classified as Pathogenic.
GeneDx	RCV002286743	SCV002577029	pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 7959691, 34224960, 17411426, 27777639)
Ambry Genetics	RCV001186209	SCV002696119	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-14	criteria provided, single submitter	clinical testing	The p.S457* pathogenic mutation (also known as c.1370C>A), located in coding exon 10 of the APC gene, results from a C to A substitution at nucleotide position 1370. This changes the amino acid from a serine to a stop codon within coding exon 10. This alteration has been reported in multiple patients with a clinical diagnosis of FAP or AFAP (Wallis YL et al. Hum. Genet., 1994 Nov;94:543-8; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2). 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.
Myriad Genetics, Inc.	RCV002524125	SCV004045762	pathogenic	Familial adenomatous polyposis 1	2023-05-01	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501164	SCV000591071	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser457X variant results in a stop codon at postion Ser457 which is predicted to cause premature truncation of the protein product. This is a loss of function DNA variant and loss of function is an established disease mechanism for the APC gene. In addition, this variant has been previously reported in individuals with familial adenomatous polyposis (FAP) (Wallis_1994_7959691, Friedl_2005_20223039, Stekrova_2007_17411426). In summary, based on the above information this variant meets our criteria for being Pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001643225	SCV001852756	pathogenic	Colonic neoplasm	2021-09-12	no assertion criteria provided	clinical testing