ClinVar Genomic variation as it relates to human health
NM_000455.5(STK11):c.817G>A (p.Ala273Thr)
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(6); Likely benign(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000455.5(STK11):c.817G>A (p.Ala273Thr)
Variation ID: 142052 Accession: VCV000142052.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.3 19: 1221295 (GRCh38) [ NCBI UCSC ] 19: 1221294 (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 Mar 17, 2018 May 1, 2024 Dec 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000455.5:c.817G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000446.1:p.Ala273Thr missense NC_000019.10:g.1221295G>A NC_000019.9:g.1221294G>A NG_007460.2:g.36889G>A LRG_319:g.36889G>A LRG_319t1:c.817G>A LRG_319p1:p.Ala273Thr - Protein change
- A273T
- Other names
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- Canonical SPDI
- NC_000019.10:1221294:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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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Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2019 | RCV000130859.9 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Dec 7, 2023 | RCV000196939.15 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000587949.5 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001356427.1 |
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
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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
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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
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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
(Jul 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696726.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The STK11 c.817G>A (p.Ala273Thr) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving the alteration of a conserved … (more)
Variant summary: The STK11 c.817G>A (p.Ala273Thr) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 0.0000101, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. However, this variant was reported in a patient with BrC (Caminsky_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)," until more definitive clinical and functional studies become available. (less)
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Likely benign
(Jul 29, 2015)
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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: SCV000905485.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
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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: SCV002057283.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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Uncertain significance
(Jun 14, 2023)
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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: SCV000569217.5
First in ClinVar: Apr 29, 2017 Last updated: Jun 24, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, but also in unaffected controls (Caminsky et al., 2016; Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 15863673, 30287823, 26898890, 26010451) (less)
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Uncertain significance
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134851.4
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
In the published literature, the variant has been reported in a woman affected with breast cancer (PMID: 26898890 (2016)). This variant was also identified in … (more)
In the published literature, the variant has been reported in a woman affected with breast cancer (PMID: 26898890 (2016)). This variant was also identified in both affected and unaffected individuals in large-scale breast cancer association studies (PMIDs: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.0000082 (2/243660 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Dec 07, 2023)
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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: SCV000254558.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 273 of the STK11 protein (p.Ala273Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 273 of the STK11 protein (p.Ala273Thr). This variant is present in population databases (rs587782199, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26898890, 30287823). ClinVar contains an entry for this variant (Variation ID: 142052). 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 95%. 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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Likely benign
(Apr 11, 2019)
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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: SCV000185758.8
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
(Jun 09, 2023)
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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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Revvity Omics, Revvity
Accession: SCV004237906.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely Benign
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Peutz-Jeghers syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004818912.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Number of individuals with the variant: 2
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Generalized juvenile polyposis/juvenile polyposis coli
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551591.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The STK11 p.Ala273Thr variant was identified in 1 of 576 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Caminsky 2016). … (more)
The STK11 p.Ala273Thr variant was identified in 1 of 576 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Caminsky 2016). The variant was also identified in dbSNP (ID: rs587782199) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x in Large intestine). The variant was not identified in MutDB, LOVD 3.0, Zhejiang University Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 2 of 241530 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33228 chromosomes (freq: 0.00003), European in 1 of 109252 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala273 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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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 |
Recurrent EGFR alterations in NTRK3 fusion negative congenital mesoblastic nephroma. | Lei L | Practical laboratory medicine | 2020 | PMID: 32490123 |
Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases. | Šimčíková D | Scientific reports | 2019 | PMID: 31819097 |
Enrichment of short mutant cell-free DNA fragments enhanced detection of pancreatic cancer. | Liu X | EBioMedicine | 2019 | PMID: 30857943 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. | Kovaleva V | Molecular cancer | 2016 | PMID: 27756406 |
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. | Caminsky NG | Human mutation | 2016 | PMID: 26898890 |
Amplicon sequencing of colorectal cancer: variant calling in frozen and formalin-fixed samples. | Betge J | PloS one | 2015 | PMID: 26010451 |
Text-mined citations for rs587782199 ...
HelpRecord last updated May 08, 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.