Submissions for variant NM_000455.5(STK11):c.397G>A (p.Val133Met)

dbSNP: rs567769257

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161000	SCV000211710	uncertain significance	not provided	2014-07-02	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.397G>A at the cDNA level, p.Val133Met (V133M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Val133Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. STK11 Val133Met occurs at a position that is highly conserved through vertebrates and is located in the protein kinase domain (UniProt) and in the site of catalysis (Hearle 2006). 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 Val133Met is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl	RCV000411610	SCV000488051	uncertain significance	Peutz-Jeghers syndrome	2015-12-16	criteria provided, single submitter	clinical testing
Invitae	RCV000411610	SCV000541134	uncertain significance	Peutz-Jeghers syndrome	2022-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 133 of the STK11 protein (p.Val133Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 182906). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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	RCV000575310	SCV000672316	likely benign	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000575310	SCV000686643	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 133 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has not been identified 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 Molecular Pathology, St. Jude Children's Research Hospital	RCV000761133	SCV000891049	uncertain significance	Hepatoblastoma	2016-12-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781888	SCV000920273	uncertain significance	not specified	2017-11-09	criteria provided, single submitter	clinical testing	Variant summary: The c.397G>A (p.Val133Met) in STK11 gene is a missense variant involves a non-conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant is located within ATP binding site on conserved domain STKc_LKB1, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant is present in the control population dataset of ExAC and gnomAD (9.459e-05; 4/ 42290 and 0.000023; 5/215188 chrs tested, respectively with a note, that this is low quality site). The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that the variant may represent a benign polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited as VUS by reputable databases/clinical laboratories. Due to the low quality of coverage in the general population datasents and a possibility of the variant call being deriven from a pseudogene, the variant was classified as VUS-Possibly Normal, until new information becomes available.
Genome-Nilou Lab	RCV000411610	SCV002057781	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575310	SCV002531690	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411610	SCV004017973	uncertain significance	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.