ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.566C>T (p.Thr189Ile) (rs587781515)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129498 SCV000184270 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000204187 SCV000260775 uncertain significance Peutz-Jeghers syndrome 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 189 of the STK11 protein (p.Thr189Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587781515, ExAC 0.01%). This variant has been reported in an individual with Peutz-Jegher syndrome (PMID: 24307375). ClinVar contains an entry for this variant (Variation ID: 141128). 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 C15"). 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 RCV000587196 SCV000279179 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing This variant is denoted STK11 c.566C>T at the cDNA level, p.Thr189Ile (T189I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant was observed in at least one individual ascertained for hereditary cancer testing due to a personal and/or family history who was reported to have Peutz-Jegher syndrome (Watson 2014). Another variant at the same position, STK11 Thr189Ala, was shown to have reduced phosphorylation ability and increased ability to induce apoptosis over wild type in HT1080 cells (Karuman 2001). STK11 Thr189Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the protein kinase domain at the substrate binding site where phospho-transfer is initiated (Schumacher 2005). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether STK11 Thr189Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000204187 SCV000489090 uncertain significance Peutz-Jeghers syndrome 2016-08-16 criteria provided, single submitter clinical testing
Color RCV000129498 SCV000537614 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220770 SCV000602230 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587196 SCV000696723 uncertain significance not provided 2016-03-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765431 SCV000896715 uncertain significance Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis 2018-10-31 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000587196 SCV000920676 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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