ClinVar Miner

Submissions for variant NM_000455.5(STK11):c.842C>T (p.Pro281Leu) (rs121913322)

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Total submissions: 10
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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 2018-12-07 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
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.
Invitae RCV000232126 SCV000284877 likely benign Peutz-Jeghers syndrome 2019-12-31 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
Integrated Genetics/Laboratory Corporation of America RCV000235215 SCV000696727 benign not specified 2020-02-07 criteria provided, single submitter clinical testing 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 variant allele was found at a frequency of 0.00012 in 240870 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 240 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 sequencing studies of 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 (example, Ku_2014, Preusser_2015, Han_2014, Koivunen_2008, Onozato_2007, Jeong_2017, Ohmoto_2016). Additionally a recent Japanese case control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome or HBOC. At-least two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (example, Zeqiraj_2009, Launonen_2000). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=2; VUS, n=4). Based on the evidence outlined above, the variant was re-classified as benign.
Counsyl RCV000232126 SCV000784770 uncertain significance Peutz-Jeghers syndrome 2017-05-26 criteria provided, single submitter clinical testing
Mendelics RCV000232126 SCV000839417 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000130951 SCV000902811 benign Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030733 SCV001193749 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Database of Curated Mutations (DoCM) RCV000419015 SCV000505695 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only

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