ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.842C>T (p.Pro281Leu) (rs121913322)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130951 SCV000185865 likely benign Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Color RCV000130951 SCV000902811 benign Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing
Counsyl RCV000232126 SCV000784770 uncertain significance Peutz-Jeghers syndrome 2017-05-26 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000419015 SCV000505695 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
GeneDx RCV000235215 SCV000211716 uncertain significance not specified 2017-05-30 criteria provided, single submitter clinical testing Although this variant has not been reported as a germline pathogenic variant to our knowledge, STK11 Pro281Leu has been published as a somatic variant in several different tumor types including lung, ovary, colorectal, gastric, and hepatocellular (Dong 1998, Nishioka 1999, Kim 2004, Onozato 2007, Koivunen 2008, Okuda 2011, Lee 2012). An in vitro autophosphorylation assay found that this variant abolished protein kinase activity (Launonen 2000). STK11 Pro281Leu was observed at an allele frequency of 0.17% (11/6582) in East Asian individuals in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Pro281Leu occurs at a position that is conserved through mammals and is located in 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 information, it is unclear whether STK11 Pro281Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000235215 SCV000696727 likely benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: STK11 c.842C>T (p.Pro281Leu) results in a non-conservative amino acid change located in the catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 256 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.842C>T variant has been reported in the literature in individuals affected with multiple types of cancers (lung, colon, salivary gland, etc) without confirmation as a germline variant and also in one individual with pancreatic ductal adenocarcinoma as a germline variant (Ohmoto_2016). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome or HBOC. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Zeqiraj_2009, Launonen_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant with conflicting assessments (2x VUS, 2x Likely Benign). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000232126 SCV000284877 likely benign Peutz-Jeghers syndrome 2017-11-29 criteria provided, single submitter clinical testing
Mendelics RCV000232126 SCV000839417 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235215 SCV000602238 uncertain significance not specified 2017-01-03 criteria provided, single submitter clinical testing

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