ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7472T>C (p.Met2491Thr) (rs369075403)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164068 SCV000214678 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000226252 SCV000282823 uncertain significance Familial adenomatous polyposis 1 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2491 of the APC protein (p.Met2491Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs369075403, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 184756). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000590327 SCV000566115 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing This variant is denoted APC c.7472T>C at the cDNA level, p.Met2491Thr (M2491T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as a pathogenic germline variant or benign polymorphism. However, it has been reported as a somatic variant in at least one extrauterine M?llerian carcinoma (Ritterhouse 2016). APC Met2491Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Met2491Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164068 SCV000681869 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590327 SCV000694117 uncertain significance not provided 2016-03-25 criteria provided, single submitter clinical testing Variant summary: The APC c.7472T>C variant affects a conserved nucleotide, resulting in an amino acid change from Met to Thr. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index); however, it has not been evaluated for functional impact by in vivo/vitro studies. This variant was found in 1/121366 control chromosomes at a frequency of 0.0000082, which does not significantly exceed maximal expected frequency of a pathogenic APC allele (0.0000602). In addition, one clinical laboratory classified this variant as a VUS. The variant of interest has been reported in one colorectal polyposis patient to co-occur with an unspecified APC truncating variant (Jones_Thesis_2008), suggesting that this APC variant may be benign. However, in the absence of functional studies, and detailed clinical and genotype information, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000226252 SCV000784802 uncertain significance Familial adenomatous polyposis 1 2016-12-23 criteria provided, single submitter clinical testing

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