ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.31A>G (p.Met11Val) (rs753834428)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222194 SCV000278097 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000232648 SCV000284863 uncertain significance Peutz-Jeghers syndrome 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 11 of the STK11 protein (p.Met11Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. While this variant is present in population databases (rs753834428), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 233673). 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 valine amino acid residue is also 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. 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 RCV000485960 SCV000572439 uncertain significance not provided 2016-12-06 criteria provided, single submitter clinical testing This variant is denoted STK11 c.31A>G at the cDNA level, p.Met11Val (M11V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in at least one individual with triple negative breast cancer (Couch 2015). STK11 Met11Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. STK11 Met11Val occurs at a position that is not conserved and is not located in a known functional domain (Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Met11Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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