ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1045G>A (p.Glu349Lys) (rs553752236)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115592 SCV000149501 uncertain significance not provided 2017-10-19 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1045G>A at the cDNA level, p.Glu349Lys (E349K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as a germline variant. However, it has been reported as a somatic variant in an individual with medullary thyroid cancer and in an individual with cervical cancer (Ji 2015, Lou 2015). STK11 Glu349Lys was observed at an allele frequency of 0.041% (3/7388) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Glu349Lys occurs at a position that is not conserved and is not located in a known functional domain. 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 Glu349Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000476845 SCV000541151 uncertain significance Peutz-Jeghers syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 349 of the STK11 protein (p.Glu349Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs553752236, ExAC 0.04%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 127697). 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.
Ambry Genetics RCV000573750 SCV000672327 likely benign Hereditary cancer-predisposing syndrome 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign)
Color RCV000573750 SCV000686581 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781887 SCV000920271 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The STK11 c.1045G>A (p.Glu349Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 13/273218 control chromosomes in gnomAD at a frequency of 0.0000476, which is approximately 8 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. This variant was reported in one case of medullary thyroid cancer as a somatic variant (Ji_2015). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761075 SCV000890990 uncertain significance B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified 2016-08-08 no assertion criteria provided clinical testing

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