ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4478C>T (p.Thr1493Met) (rs374892194)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130087 SCV000184915 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000590777 SCV000209526 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing This variant is denoted APC c.4478C>T at the cDNA level, p.Thr1493Met (T1493M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has been observed in one healthy control individual (Azzopardi 2008). APC Thr1493Met was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1493Met occurs at a position that is conserved across species and is located in the the 20-aa repeat B-catenin down-regulating domain (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Thr1493Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000228695 SCV000282755 uncertain significance Familial adenomatous polyposis 1 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1493 of the APC protein (p.Thr1493Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs374892194, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 141521). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Counsyl RCV000228695 SCV000488216 uncertain significance Familial adenomatous polyposis 1 2016-01-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590777 SCV000694054 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing Variant summary: The APC c.4478C>T (p.Thr1493Met) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 5/123012 control chromosomes at a frequency of 0.0000406, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). The variant was detected in one breast tumor sample and in a control individual in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000590777 SCV000859960 uncertain significance not provided 2018-03-21 criteria provided, single submitter clinical testing
Color RCV000130087 SCV000905985 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-20 criteria provided, single submitter clinical testing

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