ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.397G>A (p.Val133Met) (rs567769257)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161000 SCV000211710 uncertain significance not provided 2014-07-02 criteria provided, single submitter clinical testing This variant is denoted STK11 c.397G>A at the cDNA level, p.Val133Met (V133M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Val133Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. STK11 Val133Met occurs at a position that is highly conserved through vertebrates and is located in the protein kinase domain (UniProt) and in the site of catalysis (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Val133Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000411610 SCV000488051 uncertain significance Peutz-Jeghers syndrome 2015-12-16 criteria provided, single submitter clinical testing
Invitae RCV000411610 SCV000541134 uncertain significance Peutz-Jeghers syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 133 of the STK11 protein (p.Val133Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs567769257, ExAC 0.03%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 182906). 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.
Ambry Genetics RCV000575310 SCV000672316 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000575310 SCV000686643 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781888 SCV000920273 uncertain significance not specified 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The c.397G>A (p.Val133Met) in STK11 gene is a missense variant involves a non-conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant is located within ATP binding site on conserved domain STKc_LKB1, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of ExAC and gnomAD (9.459e-05; 4/ 42290 and 0.000023; 5/215188 chrs tested, respectively with a note, that this is low quality site). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that the variant may represent a benign polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as VUS by reputable databases/clinical laboratories. Due to the low quality of coverage in the general population datasents and a possibility of the variant call being deriven from a pseudogene, the variant was classified as VUS-Possibly Normal, until new information becomes available.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761133 SCV000891049 uncertain significance Hepatoblastoma 2016-12-05 no assertion criteria provided clinical testing

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