ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.559G>A (p.Gly187Ser) (rs587782032)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130480 SCV000185349 likely benign Hereditary cancer-predisposing syndrome 2017-05-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification,Other data supporting benign classification
Invitae RCV000198594 SCV000254553 uncertain significance Peutz-Jeghers syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 187 of the STK11 protein (p.Gly187Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs587782032, ExAC 0.02%). This variant has been reported in an individual affected with triple negative breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 141815). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000590446 SCV000279178 uncertain significance not provided 2017-08-27 criteria provided, single submitter clinical testing This variant is denoted STK11 c.559G>A at the cDNA level, p.Gly187Ser (G187S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant was observed in at least one individual with triple negative breast cancer (Couch 2015). STK11 Gly187Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly187Ser occurs at a position that is not conserved and is located in the protein kinase domain and in the region required for binding of substrate and initiation of phospho transfer (UniProt, Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Gly187Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855607 SCV000696722 likely benign not specified 2019-07-10 criteria provided, single submitter clinical testing Variant summary: STK11 c.559G>A (p.Gly187Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR039154) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284338 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome (PJS) phenotype (6.3e-06), strongly suggesting that the variant is benign. Though the variant, c.559G>A, has been reported in the literature in individuals affected with lung-, and breast cancer (Kim_2010, Couch_2015, Momozawa_ 2018), in one of these cases it was noted that the affected patient did not have any clinical manifestations of PJS (Kim_2010); moreover the variant was also reported in multiple healthy controls (Kim_2010, Momozawa_ 2018 and in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000198594 SCV000784804 uncertain significance Peutz-Jeghers syndrome 2017-01-03 criteria provided, single submitter clinical testing
Mendelics RCV000198594 SCV000839415 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000130480 SCV000902824 likely benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing

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