ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1685C>T (p.Thr562Met) (rs587783034)

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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 RCV000222854 SCV000274259 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000144570 SCV000282700 uncertain significance Familial adenomatous polyposis 1 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 562 of the APC protein (p.Thr562Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs587783034, ExAC 0.02%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 156480). 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: "Possibly 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.
GeneDx RCV000766534 SCV000569774 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted APC c.1685C>T at the cDNA level, p.Thr562Met (T562M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant was observed in at least two individuals with colorectal cancer (DeRycke 2017). APC Thr562Met was observed at an allele frequency of 0.07% (14/18,852) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Armadillo Region (Azzopardi 2008). 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 Thr562Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000222854 SCV000681482 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000485323 SCV000731502 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing The p.Thr562Met variant in APC has not been previously reported in individuals w ith familial adenomatous polyposis or other APC-associated disorders but has bee n reported in ClinVar (Variation ID: 156480). It has also been identified in 2/8 618 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs587783034). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr562Met variant is uncertain.
Counsyl RCV000144570 SCV000785064 uncertain significance Familial adenomatous polyposis 1 2017-04-04 criteria provided, single submitter clinical testing
Pathway Genomics RCV000144570 SCV000189866 uncertain significance Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing

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