ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.841C>A (p.Pro281Thr) (rs377208033)

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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 RCV000132358 SCV000187447 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000219471 SCV000279182 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing This variant is denoted STK11 c.841C>A at the cDNA level, p.Pro281Thr (P281T) at the protein level, and results in the change of a Proline to a Threonine (CCG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Pro281Thr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Pro281Thr occurs at a position that is conserved in mammals and is located within the protein kinase domain (UniProt). 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 Pro281Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000468995 SCV000541124 uncertain significance Peutz-Jeghers syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 281 of the STK11 protein (p.Pro281Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs377208033, ExAC 0.01%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142891). 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.
Color RCV000132358 SCV000686693 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing

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