ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.976C>A (p.Pro326Thr) (rs771632414)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163989 SCV000214589 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000766875 SCV000279185 uncertain significance not provided 2015-11-24 criteria provided, single submitter clinical testing This variant is denoted STK11 c.976C>A at the cDNA level, p.Pro326Thr (P326T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Pro326Thr was not observed in approximately 6,300 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 Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Pro326Thr occurs at a position that is not conserved and is not located in a known functional domain (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 Pro326Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217261 SCV000602248 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing
Invitae RCV000553557 SCV000629164 uncertain significance Peutz-Jeghers syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 326 of the STK11 protein (p.Pro326Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 184692). 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.
Counsyl RCV000553557 SCV000786018 uncertain significance Peutz-Jeghers syndrome 2018-02-01 criteria provided, single submitter clinical testing
Color RCV000163989 SCV000910056 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing

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