ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1276C>G (p.Arg426Gly) (rs587782687)

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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 RCV000132118 SCV000187186 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Counsyl RCV000410170 SCV000488871 uncertain significance Peutz-Jeghers syndrome 2016-07-08 criteria provided, single submitter clinical testing
GeneDx RCV000485540 SCV000570750 uncertain significance not provided 2016-06-22 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1276C>G at the cDNA level, p.Arg426Gly (R426G) at the protein level, and results in the change of an Arginine to a Glycine (CGG>GGG). This variant was observed in an individual with malignant pleural mesothelioma (Bueno 2016). STK11 Arg426Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Arg426Gly occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located within the C-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Arg426Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000410170 SCV000629091 uncertain significance Peutz-Jeghers syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 426 of the STK11 protein (p.Arg426Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 142743). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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