VCV000403750.18 - ClinVar

NM_000455.5(STK11):c.842dup (p.Leu282fs)

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.

(5)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

NM_000455.5(STK11):c.842dup (p.Leu282fs)

Variation ID: 403750 Accession: VCV000403750.18

Type and length

Duplication, 1 bp

Location

Cytogenetic: 19p13.3 19: 1221314-1221315 (GRCh38) [ NCBI UCSC ] 19: 1221313-1221314 (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	Jul 1, 2017	May 1, 2024	Nov 12, 2023
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000455.5:c.842dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000446.1:p.Leu282fs	frameshift
NM_000455.5:c.842dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000455.4:c.842dupC
NC_000019.10:g.1221320dup
NC_000019.9:g.1221319dup
NG_007460.2:g.36914dup
LRG_319:g.36914dup
LRG_319t1:c.842dup	LRG_319p1:p.Leu282fs

... more HGVS ... less HGVS

Protein change

L282fs

Other names

Canonical SPDI

NC_000019.10:1221314:CCCCCC:CCCCCCC

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.

Links

ClinGen: CA16616021 dbSNP: rs121913321 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	Pathogenic (1)	criteria provided, single submitter	Sep 18, 2023	RCV000492505.3
Peutz-Jeghers syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 12, 2023	RCV000474843.11
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 23, 2020	RCV001566266.3

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.
Pathogenic (Sep 30, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Peutz-Jeghers syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001983473.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Publications: PubMed (2) PubMed: 16287113‚ 9760200 Comment: Variant summary: STK11 c.842dupC (p.Leu282AlafsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: STK11 c.842dupC (p.Leu282AlafsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Peutz-Jeghers Syndrome in HGMD. The variant allele was found at a frequency of 4.1e-06 in 241672 control chromosomes. c.842dupC has been reported in the literature in individuals affected with Peutz-Jeghers Syndrome (example, Nakagawa_1998, and Aretz_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (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: SCV002057380.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Pathogenic (Nov 12, 2023)	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: SCV000541102.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 15188174‚ 16287113‚ 9760200 Comment: This sequence change creates a premature translational stop signal (p.Leu282Alafs3) in the STK11 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu282Alafs3) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). 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 premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9760200, 16287113). ClinVar contains an entry for this variant (Variation ID: 403750). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 18, 2023)	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: SCV000580906.6 First in ClinVar: Jul 01, 2017 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 15863673‚ 16110486‚ 16287113‚ 24604241‚ 32462036‚ 9760200 Comment: The c.842dupC pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a duplication of C at nucleotide position 842, causing a … (more) The c.842dupC pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a duplication of C at nucleotide position 842, causing a translational frameshift with a predicted alternate stop codon (p.L282Afs*3). This pathogenic mutation has been detected in numerous unrelated families with PJS (Nakagawa H et al. Hum Genet. 1998 Aug;103:168-72; Schumacher V et al. J Med Genet. 2005 May;42:428-35; Aretz S et al. Hum Mutat. 2005 Dec;26:513-9; Launonen V. Hum Mutat. 2005 Oct;26:291-7; Dai L et al. Dig Dis Sci. 2014 Aug;59:1856-61; Wu BD et al. Biomed Res Int. 2020 May;2020:9159315). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Mar 23, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001789761.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32462036, 30092773, 9760200, 30689838, 28152038) (less)

Comment:

Variant summary: STK11 c.842dupC (p.Leu282AlafsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Peutz-Jeghers Syndrome in HGMD. The variant allele was found at a frequency of 4.1e-06 in 241672 control chromosomes. c.842dupC has been reported in the literature in individuals affected with Peutz-Jeghers Syndrome (example, Nakagawa_1998, and Aretz_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Leu282Alafs*3) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). 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 premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 9760200, 16287113). ClinVar contains an entry for this variant (Variation ID: 403750). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.842dupC pathogenic mutation, located in coding exon 6 of the STK11 gene, results from a duplication of C at nucleotide position 842, causing a translational frameshift with a predicted alternate stop codon (p.L282Afs*3). This pathogenic mutation has been detected in numerous unrelated families with PJS (Nakagawa H et al. Hum Genet. 1998 Aug;103:168-72; Schumacher V et al. J Med Genet. 2005 May;42:428-35; Aretz S et al. Hum Mutat. 2005 Dec;26:513-9; Launonen V. Hum Mutat. 2005 Oct;26:291-7; Dai L et al. Dig Dis Sci. 2014 Aug;59:1856-61; Wu BD et al. Biomed Res Int. 2020 May;2020:9159315). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32462036, 30092773, 9760200, 30689838, 28152038)

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
Clinical and Genetic Analyses of 38 Chinese Patients with Peutz-Jeghers Syndrome.	Wu BD	BioMed research international	2020	PMID: 32462036
Novel and recurrent mutations of STK11 gene in six Chinese cases with Peutz-Jeghers syndrome.	Dai L	Digestive diseases and sciences	2014	PMID: 24604241
High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome.	Aretz S	Human mutation	2005	PMID: 16287113
Mutations in the human LKB1/STK11 gene.	Launonen V	Human mutation	2005	PMID: 16110486
STK11 genotyping and cancer risk in Peutz-Jeghers syndrome.	Schumacher V	Journal of medical genetics	2005	PMID: 15863673
Relative frequency and morphology of cancers in STK11 mutation carriers.	Lim W	Gastroenterology	2004	PMID: 15188174
Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome.	Nakagawa H	Human genetics	1998	PMID: 9760200

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668976.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005093986.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs121913321 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000455.5(STK11):c.842dup (p.Leu282fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs121913321 ...