ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.817G>A (p.Ala273Thr) (rs587782199)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130859 SCV000185758 likely benign Hereditary cancer-predisposing syndrome 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign)
Invitae RCV000196939 SCV000254558 uncertain significance Peutz-Jeghers syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 273 of the STK11 protein (p.Ala273Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587782199, ExAC 0.002%). This variant has been observed in an individual affected with breast cancer (PMID: 26898890). ClinVar contains an entry for this variant (Variation ID: 142052). 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.
GeneDx RCV000587949 SCV000569217 uncertain significance not provided 2017-12-06 criteria provided, single submitter clinical testing This variant is denoted STK11 c.817G>A at the cDNA level, p.Ala273Thr (A273T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Ala273Thr was not observed at a significant allele frequency 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 Ala273Thr is located in the protein kinase domain (UniProt). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Ala273Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587949 SCV000696726 uncertain significance not provided 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The STK11 c.817G>A (p.Ala273Thr) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 0.0000101, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. However, this variant was reported in a patient with BrC (Caminsky_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until more definitive clinical and functional studies become available.
Color RCV000130859 SCV000905485 likely benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing

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