VCV000142891.30 - ClinVar

NM_000455.5(STK11):c.841C>A (p.Pro281Thr)

Germline

Classification

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000455.5(STK11):c.841C>A (p.Pro281Thr)

Variation ID: 142891 Accession: VCV000142891.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.3 19: 1221319 (GRCh38) [ NCBI UCSC ] 19: 1221318 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 29, 2016	May 1, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000455.5:c.841C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000446.1:p.Pro281Thr	missense
NC_000019.10:g.1221319C>A
NC_000019.9:g.1221318C>A
NG_007460.2:g.36913C>A
LRG_319:g.36913C>A
LRG_319t1:c.841C>A	LRG_319p1:p.Pro281Thr

... more HGVS ... less HGVS

Protein change

P281T

Other names

Canonical SPDI

NC_000019.10:1221318:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00005

Exome Aggregation Consortium (ExAC) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA023300 dbSNP: rs377208033 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
STK11		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2394	2672

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 Help 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.
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Sep 9, 2022	RCV000132358.23
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Oct 12, 2022	RCV000219471.14
Peutz-Jeghers syndrome	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000468995.24

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.
Uncertain significance (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peutz-Jeghers syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002057857.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Uncertain significance (Feb 02, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002526946.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The STK11 c.841C>A (p.P281T) variant has been reported in heterozygosity in at least two individuals with colorectal cancer (PMID: 28135145, 29458332). This variant was observed … (more) The STK11 c.841C>A (p.P281T) variant has been reported in heterozygosity in at least two individuals with colorectal cancer (PMID: 28135145, 29458332). This variant was observed in 13/272920 chromosomes across all populations in the large and broad cohorts in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 142891). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 28135145‚ 29458332
Uncertain significance (Apr 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peutz-Jeghers syndrome Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579146.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM2_SUP, BP4	Number of individuals with the variant: 2 Sex: female
Uncertain significance (Oct 12, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279182.13 First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal cancer … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal cancer in published literature (Yurgelun et al., 2017; Dominguez-Valentin et al., 2018); This variant is associated with the following publications: (PMID: 28135145, 29458332, 15863673, 33845213) (less)
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009163.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Peutz-Jeghers syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000541124.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 28492532‚ 28135145‚ 29458332 Comment: This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the STK11 protein (p.Pro281Thr). … (more) This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the STK11 protein (p.Pro281Thr). This variant is present in population databases (rs377208033, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145, 29458332). ClinVar contains an entry for this variant (Variation ID: 142891). 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)
Likely Benign (Aug 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Peutz-Jeghers syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004818922.1 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)	Number of individuals with the variant: 3
Likely benign (Sep 09, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187447.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 28135145‚ 28726808‚ 29458332 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)
Likely benign (Aug 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000686693.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024
not provided (-)	no classification provided Method: phenotyping only	Peutz-Jeghers syndrome Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749757.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Uncertain significance and reported on 06-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Uncertain significance and reported on 06-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-06-05 Testing laboratory interpretation: Uncertain significance

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and/or family history of colorectal cancer in published literature (Yurgelun et al., 2017; Dominguez-Valentin et al., 2018); This variant is associated with the following publications: (PMID: 28135145, 29458332, 15863673, 33845213)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the STK11 protein (p.Pro281Thr). This variant is present in population databases (rs377208033, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145, 29458332). ClinVar contains an entry for this variant (Variation ID: 142891). 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.

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 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.

Comment:

Variant interpreted as Uncertain significance and reported on 06-05-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of genetic variants for clinical management of familial colorectal tumors.	Dominguez-Valentin M	BMC medical genetics	2018	PMID: 29458332
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.	Chaffee KG	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28726808
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.	Yurgelun MB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28135145

Text-mined citations for rs377208033 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000455.5(STK11):c.841C>A (p.Pro281Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377208033 ...