NM_000455.5(STK11):c.125G>T (p.Arg42Leu) AND Peutz-Jeghers syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Oct 29, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000460664.19

Allele description [Variation Report for NM_000455.5(STK11):c.125G>T (p.Arg42Leu)]

NM_000455.5(STK11):c.125G>T (p.Arg42Leu)

Gene:

STK11:serine/threonine kinase 11 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_000455.5(STK11):c.125G>T (p.Arg42Leu)

HGVS:

NC_000019.10:g.1207038G>T
NG_007460.2:g.22632G>T
NM_000455.5:c.125G>TMANE SELECT
NP_000446.1:p.Arg42Leu
NP_000446.1:p.Arg42Leu
LRG_319t1:c.125G>T
LRG_319:g.22632G>T
LRG_319p1:p.Arg42Leu
NC_000019.9:g.1207037G>T
NM_000455.4:c.125G>T

Protein change:

R42L

Links:

dbSNP: rs148830698

NCBI 1000 Genomes Browser:

rs148830698

Molecular consequence:

NM_000455.5:c.125G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Peutz-Jeghers syndrome (PJS)
Synonyms:: Polyposis, hamartomatous intestinal; Polyps-and-spots syndrome; Peutz-Jeghers polyposis; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008280; MeSH: D010580; MedGen: C0031269; Orphanet: 2869; OMIM: 175200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000541143	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Oct 29, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000786581	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (May 29, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17711506, 24793789 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV002057229	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004017943	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Apr 12, 2023)	unknown	clinical testing	Citation Link,
SCV004816319	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17711506, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

The MZF1/c-MYC axis mediates lung adenocarcinoma progression caused by wild-type lkb1 loss.

Tsai LH, Wu JY, Cheng YW, Chen CY, Sheu GT, Wu TC, Lee H.

Oncogene. 2015 Mar 26;34(13):1641-9. doi: 10.1038/onc.2014.118. Epub 2014 May 5.

PubMed [citation]

PMID:: 24793789

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000541143.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000786581.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002057229.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004017943.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004816319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces arginine with leucine at codon 42 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with lung cancer (PMID: 17711506). This variant has been identified in 15/248194 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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