ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3875C>T (p.Thr1292Met) (rs371113837)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129039 SCV000172950 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000198586 SCV000254012 uncertain significance Familial adenomatous polyposis 1 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1292 of the APC protein (p.Thr1292Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs371113837, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with familial adenomatous polyposis and colorectal cancer (PMID: 1338764, 25559809). ClinVar contains an entry for this variant (Variation ID: 133519). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657042 SCV000293018 uncertain significance not provided 2018-08-27 criteria provided, single submitter clinical testing This variant is denoted APC c.3875C>T at the cDNA level, p.Thr1292Met (T1292M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been reported in an individual with colorectal cancer whose father was also diagnosed with late-onset colorectal cancer (Chubb 2015) and in an individual with a clinical diagnosis of FAP; however this variant was reported to not segregate with disease in the family (Nagase 1992). APC Thr1292Met was also identified in at least one individual with breast cancer (Tung 2015) as well as 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the Bodian et al. study were younger than 50 years old thus the unaffected status of this individual may not be significant. APC Thr1292Met was observed at an allele frequency of 0.021% (5/24,030) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in a beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Thr1292Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129039 SCV000681637 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000198586 SCV000803460 uncertain significance Familial adenomatous polyposis 1 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for familial adenomatous polyposis 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657042 SCV000888738 uncertain significance not provided 2018-04-29 criteria provided, single submitter clinical testing
ITMI RCV000120026 SCV000084157 not provided not specified 2013-09-19 no assertion provided reference population

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.