Submissions for variant NM_000038.6(APC):c.487C>T (p.Gln163Ter)

dbSNP: rs863225362

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517332	SCV000647543	pathogenic	Familial adenomatous polyposis 1	2022-05-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 217991). This premature translational stop signal has been observed in individual(s) with colonic adenomas and colorectal cancer (PMID: 9585611). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln163*) 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).
GeneDx	RCV000202083	SCV000779341	pathogenic	not provided	2024-07-25	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: 18829530, 25525159, 11960572, 16461775, 28199314, 9585611, 15300853, 18782851, 23159591, 11247895, 20685668, 17963004)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000500940	SCV000916510	pathogenic	Familial multiple polyposis syndrome	2021-04-08	criteria provided, single submitter	clinical testing	Variant summary: APC c.487C>T (p.Gln163X) 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 245984 control chromosomes. c.487C>T has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (example, Scott_2001, Soravia_1998, Sieber_2006). These data indicate that the variant is very likely to be 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 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001023190	SCV001185028	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-01	criteria provided, single submitter	clinical testing	The p.Q163* pathogenic mutation (also known as c.487C>T), located in exon 4 of the APC gene, results from a C to T substitution at nucleotide position 487. This changes the amino acid from a glutamine to a stop codon within exon 4. This variant has been reported in multiple individuals with features consistent with APC-associated polyposis conditions (Abrams HR et al. ACG Case Rep J. 2020 Oct;7(10):e00469; Ambry internal data). This mutation was also identified in six members of a family with hereditary predisposition to colonic adenomas and colorectal cancer. Two family members were diagnosed with colorectal cancer, one at the age of 35 and one at age 60, and four family members were found to have numerous adenomatous colon polyps (Soravia et al. Am. J. Hum. Genet. 1998;62:1290-1301). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.	RCV002517332	SCV004044725	pathogenic	Familial adenomatous polyposis 1	2023-04-26	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202083	SCV000257007	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202083	SCV000591034	uncertain significance	not provided		no assertion criteria provided	clinical testing