ClinVar Miner

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

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Total submissions: 7
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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 likely benign Peutz-Jeghers syndrome 2020-10-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573750 SCV000672327 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign)
Color Health, Inc RCV000573750 SCV000686581 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 349 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with lung cancer (PMID: 32320754) and medullary thyroid cancer (PMID: 26295973). This variant has been identified in 13/275920 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761075 SCV000890990 uncertain significance B Lymphoblastic Leukemia/Lymphoma, Not Otherwise Specified 2016-08-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285381 SCV001471800 uncertain significance none provided 2020-02-18 criteria provided, single submitter clinical testing The STK11 c.1045G>A; p.Glu349Lys variant (rs553752236) has been reported in an individual with breast cancer but also in a healthy control (Momozawa 2018). This variant is reported in the ClinVar database (Variation ID: 127697). It is found in the general population with an overall allele frequency of 0.005% (13/275920 alleles, including 1 homozygote) in the Genome Aggregation Database. The glutamate at codon 349 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083.

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