ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1127A>C (p.Glu376Ala) (rs373888280)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586344 SCV000149503 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1127A>C at the cDNA level, p.Glu376Ala (E376A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. STK11 Glu376Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). STK11 Glu376Ala is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Glu376Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115594 SCV000184985 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000205503 SCV000260042 uncertain significance Peutz-Jeghers syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 376 of the STK11 protein (p.Glu376Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs373888280, ExAC 0.03%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 127698). 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 RCV000115594 SCV000686590 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855606 SCV000696702 uncertain significance not specified 2019-08-05 criteria provided, single submitter clinical testing Variant summary: STK11 c.1127A>C (p.Glu376Ala) results in a non-conservative amino acid change in 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 3.7e-05 in 273182 control chromosomes (gnomAD). The observed variant frequency is approximately 6 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 benign. c.1127A>C has been reported in the literature in a cohort of children with malignant pediatric tumors (Chan _2018). However, this report does not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence become available.
Counsyl RCV000205503 SCV000785631 uncertain significance Peutz-Jeghers syndrome 2017-10-17 criteria provided, single submitter clinical testing

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