ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1258G>A (p.Ala420Thr) (rs762482152)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226740 SCV000284855 uncertain significance Peutz-Jeghers syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 420 of the STK11 protein (p.Ala420Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs762482152, ExAC 0.1%). This variant has been reported in an individual affected with ovarian cancer, who was suspected of having Peutz-Jeghers syndrome (PMID: 19145097). ClinVar contains an entry for this variant (Variation ID: 237794). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455443 SCV000540467 uncertain significance not specified 2016-10-26 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD in a patient with Peutz-Jeghers (no access to paper). It is present in ExAC at a MaxMAF of 0.1% (1/948). AA is not conserved - 5 mammals and 15 non-mammals have a Thr at this position. Predicted to be benign by multiple prediction tools.
GeneDx RCV000766974 SCV000568653 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1258G>A at the cDNA level, p.Ala420Thr (A420T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been reported in an individual suspected of having Peutz-Jeghers syndrome (Heinritz 2008). STK11 Ala420Thr was not observed in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Ala420Thr 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 STK11 Ala420Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569699 SCV000664306 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000569699 SCV000911846 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766974 SCV001134838 uncertain significance not provided 2019-08-21 criteria provided, single submitter clinical testing

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