ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1087A>G (p.Thr363Ala) (rs764458789)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564324 SCV000672334 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000479121 SCV000566792 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1087A>G at the cDNA level, p.Thr363Ala (T363A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Alexander et al. (2010) demonstrated that this variant was not able to be phosphorylated by ATM in response to oxidative stress; however, Ui et al. (2014) subsequently found that phosphorylation may not be required for protein recruitment to double strand break sites. STK11 Thr363Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the c-terminal region (Daniell 2017). 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 STK11 Thr363Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000685209 SCV000812682 uncertain significance Peutz-Jeghers syndrome 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 363 of the STK11 protein (p.Thr363Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs764458789, ExAC 0.01%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 419166). Experimental studies have shown that this missense change abrogates phosphorylation of STK11 at the p.Thr363 residue by ATM, ATR and DNA-dependent protein kinases in response to laser irradiation-induced DNA damage (PMID: 23584481). However, its clinical significance is uncertain, as phosphorylation at this residue may not be required for the recruitment of the STK11 protein to the DNA double-strand break sites (PMID: 23584481). 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.
Mendelics RCV000685209 SCV000839426 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing

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