NM_000455.5(STK11):c.559G>A (p.Gly187Ser) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Aug 15, 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:: RCV000855607.8

Allele description [Variation Report for NM_000455.5(STK11):c.559G>A (p.Gly187Ser)]

NM_000455.5(STK11):c.559G>A (p.Gly187Ser)

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.559G>A (p.Gly187Ser)

HGVS:

NC_000019.10:g.1220467G>A
NG_007460.2:g.36061G>A
NM_000455.5:c.559G>AMANE SELECT
NP_000446.1:p.Gly187Ser
NP_000446.1:p.Gly187Ser
LRG_319t1:c.559G>A
LRG_319:g.36061G>A
LRG_319p1:p.Gly187Ser
NC_000019.9:g.1220466G>A
NM_000455.4:c.559G>A
p.G187S

Protein change:

G187S

Links:

dbSNP: rs587782032

NCBI 1000 Genomes Browser:

rs587782032

Molecular consequence:

NM_000455.5:c.559G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696722	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 10, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25452441, 20082862, 30287823 Citation Link,
SCV002761023	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003840088	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Uncertain significance (Aug 29, 2022)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696722

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 10, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002761023

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 15, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003840088

Genetic Services Laboratory, University of Chicago

no assertion criteria provided

Uncertain significance
(Aug 29, 2022)

germline

clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.

Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, et al.

J Clin Oncol. 2015 Feb 1;33(4):304-11. doi: 10.1200/JCO.2014.57.1414. Epub 2014 Dec 1.

PubMed [citation]

PMID:: 25452441
PMCID:: PMC4302212

LKB1 mutations are extremely rare in Korean non-small cell lung cancers.

Kim MJ, Jin G, Jheon HS, Lee SY, Cha SI, Kim CH, Jung TH, Park JY.

Cancer Genet Cytogenet. 2010 Jan 15;196(2):204-6. doi: 10.1016/j.cancergencyto.2009.09.020. No abstract available.

PubMed [citation]

PMID:: 20082862

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696722.2

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

Description

Variant summary: STK11 c.559G>A (p.Gly187Ser) results in a non-conservative amino acid change located in the catalytic domain (IPR039154) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284338 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome (PJS) phenotype (6.3e-06), strongly suggesting that the variant is benign. Though the variant, c.559G>A, has been reported in the literature in individuals affected with lung-, and breast cancer (Kim_2010, Couch_2015, Momozawa_ 2018), in one of these cases it was noted that the affected patient did not have any clinical manifestations of PJS (Kim_2010); moreover the variant was also reported in multiple healthy controls (Kim_2010, Momozawa_ 2018 and in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (4x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002761023.3

#	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 Genetic Services Laboratory, University of Chicago, SCV003840088.1

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

Description

DNA sequence analysis of the STK11 gene demonstrated a sequence change, c.559G>A, in exon 4 that results in an amino acid change, p.Gly187Ser. This sequence has been previously described in individuals with breast cancer, small cell lung cancers (NSCLC) and has also been described in control population (PMIDs: 25452441, 30287823, 20082862 and FLOSSIES database). This sequence change has been described in the gnomAD database in eight individuals which corresponds to a population frequency of 0.003% (dbSNP rs587782032). The p.Gly187Ser change affects a poorly conserved amino acid residue located in a domain of the STK11 protein that is known to be functional. The p.Gly187Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly187Ser change remains unknown at this time.

#	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

Last Updated: Oct 8, 2024

ClinVar

Relating variation to medicine