NM_000455.5(STK11):c.1225C>T (p.Arg409Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 17, 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:: RCV000656985.11

Allele description [Variation Report for NM_000455.5(STK11):c.1225C>T (p.Arg409Trp)]

NM_000455.5(STK11):c.1225C>T (p.Arg409Trp)

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.1225C>T (p.Arg409Trp)

HGVS:

NC_000019.10:g.1226570C>T
NG_007460.2:g.42164C>T
NM_000455.5:c.1225C>TMANE SELECT
NP_000446.1:p.Arg409Trp
NP_000446.1:p.Arg409Trp
LRG_319t1:c.1225C>T
LRG_319:g.42164C>T
LRG_319p1:p.Arg409Trp
NC_000019.9:g.1226569C>T
NM_000455.4:c.1225C>T
p.R409W

Protein change:

R409W

Links:

dbSNP: rs368466538

NCBI 1000 Genomes Browser:

rs368466538

Molecular consequence:

NM_000455.5:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000279190	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jul 23, 2020)	germline	clinical testing	Citation Link,
SCV000888639	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jan 17, 2023)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25452441, 25186627, 29785153, 34849607, 33309985, 31159747, 30287823, 30092773, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279190

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jul 23, 2020)

germline

clinical testing

Citation Link,

SCV000888639

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jan 17, 2023)

unknown

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	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

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000279190.11

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in one individual with a clinical diagnosis of Peutz-Jeghers syndrome, without a family history of disease, as well as in individuals with breast cancer (Couch 2015, Tung 2015, Goidescu 2018, Jiang 2018); Published functional studies demonstrate no damaging effect: normal P53 activity (Jiang 2018) This variant is associated with the following publications: (PMID: 30287823, 30092773, 31422574, 31159747, 29785153, 25186627, 25925381, 17676035, 25452441)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000888639.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The frequency of this variant in the general population, 0.0003 (3/10150 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 30287823 (2018), 29785153 (2018), 25452441 (2015), and 25186627 (2015)). This variant has been shown to have a wild type effect on p53 activity in vitro, however, more studies are needed to determine the global effect of this variant on STK11 protein function (PMID: 30092773 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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

Last Updated: Sep 29, 2024

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