ClinVar Genomic variation as it relates to human health
NM_000455.5(STK11):c.566C>T (p.Thr189Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(10); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000455.5(STK11):c.566C>T (p.Thr189Ile)
Variation ID: 141128 Accession: VCV000141128.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 1220474 (GRCh38) [ NCBI UCSC ] 19: 1220473 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2016 May 1, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000455.5:c.566C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000446.1:p.Thr189Ile missense NC_000019.10:g.1220474C>T NC_000019.9:g.1220473C>T NG_007460.2:g.36068C>T LRG_319:g.36068C>T LRG_319t1:c.566C>T LRG_319p1:p.Thr189Ile - Protein change
- T189I
- Other names
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- Canonical SPDI
- NC_000019.10:1220473:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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STK11 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2347 | 2619 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 23, 2023 | RCV000129498.14 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000204187.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 24, 2023 | RCV000220770.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765431.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 1, 2019 | RCV001030732.1 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 4, 2021 | RCV000587196.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Feb 14, 2018)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001530398.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Mar 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279179.8
First in ClinVar: May 29, 2016 Last updated: Apr 17, 2019 |
Comment:
Observed in individuals with reported Peutz-Jeghers syndrome and in individuals with breast cancer, but also present in unaffected control individuals (Watson 2014, Momozawa 2018, Wang … (more)
Observed in individuals with reported Peutz-Jeghers syndrome and in individuals with breast cancer, but also present in unaffected control individuals (Watson 2014, Momozawa 2018, Wang 2019); Another variant at the same position, STK11 Thr189Ala, was shown to have reduced phosphorylation ability and increased ability to induce apoptosis over wild type in HT1080 cells (Karuman 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25005758, 23724922, 24307375, 11430832, 28706299, 30287823, 30982232, 32566746) (less)
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Uncertain significance
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002057808.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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Likely benign
(May 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184270.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Carcinoma of pancreas Germ cell tumor of testis
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896715.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(May 01, 2019)
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criteria provided, single submitter
Method: research
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Hereditary breast and ovarian cancer syndrome
Affected status: yes
Allele origin:
germline
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Cancer Genomics Group, Japanese Foundation For Cancer Research
Accession: SCV001193748.2
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
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Uncertain significance
(Oct 13, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602230.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 01, 2022 |
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Uncertain significance
(Aug 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000489090.2
First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022 |
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Uncertain significance
(Apr 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018022.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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.
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Likely benign
(Oct 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696723.3
First in ClinVar: Mar 17, 2018 Last updated: Nov 20, 2023 |
Comment:
Variant summary: STK11 c.566C>T (p.Thr189Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: STK11 c.566C>T (p.Thr189Ile) 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 7.8e-05 in 283350 control chromosomes. The observed variant frequency is approximately 12-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.566C>T has been reported in the literature in individuals affected with breast cancer or pancreatic cancer (example, Momozawa_2018, Wang_2019, Yin_2022), without strong evidence for causality. This variant has also been present in control cohorts of two case-control studies of Biliary tract cancer and Breast cancer, respectively (Okawa_2023, Dorling_2021). These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 30287823, 36243179, 30982232, 24307375, 35171259, 33471991). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=11; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537614.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces threonine with isoleucine at codon 189 of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with isoleucine at codon 189 of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Peutz-Jegher syndrome (PMID: 24307375), and has been observed in both individuals with breast cancer (PMID: 30287823, 30982232), and unaffected controls (PMID: 30287823). This variant has been identified in 8/267242 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. (less)
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Uncertain significance
(Jan 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000260775.10
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 189 of the STK11 protein (p.Thr189Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 189 of the STK11 protein (p.Thr189Ile). This variant is present in population databases (rs587781515, gnomAD 0.01%). This missense change has been observed in individual(s) with Peutz-Jegher syndrome and breast cancer (PMID: 24307375, 30287823, 30982232). ClinVar contains an entry for this variant (Variation ID: 141128). 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) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 80%. 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. (less)
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Uncertain significance
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000920676.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 2019 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer. | Okawa Y | Journal of hepatology | 2023 | PMID: 36243179 |
Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. | Yin L | JAMA network open | 2022 | PMID: 35171259 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes. | Wang J | Cancer medicine | 2019 | PMID: 30982232 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Robust diagnostic genetic testing using solution capture enrichment and a novel variant-filtering interface. | Watson CM | Human mutation | 2014 | PMID: 24307375 |
The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. | Karuman P | Molecular cell | 2001 | PMID: 11430832 |
Text-mined citations for rs587781515 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.