NM_000455.5(STK11):c.1254C>G (p.Cys418Trp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 22, 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:: RCV000131151.18

Allele description [Variation Report for NM_000455.5(STK11):c.1254C>G (p.Cys418Trp)]

NM_000455.5(STK11):c.1254C>G (p.Cys418Trp)

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.1254C>G (p.Cys418Trp)

Other names:

p.C418W:TGC>TGG; p.Cys418Trp

HGVS:

NC_000019.10:g.1226599C>G
NG_007460.2:g.42193C>G
NM_000455.5:c.1254C>GMANE SELECT
NP_000446.1:p.Cys418Trp
NP_000446.1:p.Cys418Trp
LRG_319t1:c.1254C>G
LRG_319:g.42193C>G
LRG_319p1:p.Cys418Trp
NC_000019.9:g.1226598C>G
NM_000455.4:c.1254C>G
p.C418W

Protein change:

C418W

Links:

dbSNP: rs587780715

NCBI 1000 Genomes Browser:

rs587780715

Molecular consequence:

NM_000455.5:c.1254C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186093	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Nov 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000266231	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Shirts et al. (Genet Med 2016))	Uncertain significance (Nov 20, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000686608	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186093

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Nov 4, 2021)

germline

clinical testing

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

Citation Link,

SCV000266231

University of Washington Department of Laboratory Medicine, University of Washington

criteria provided, single submitter

(Shirts et al. (Genet Med 2016))

Uncertain significance
(Nov 20, 2015)

germline

clinical testing

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

SCV000686608

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP.

N Engl J Med. 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919.

PubMed [citation]

PMID:: 32459922
PMCID:: PMC7839065

Improving performance of multigene panels for genomic analysis of cancer predisposition.

Shirts BH, Casadei S, Jacobson AL, Lee MK, Gulsuner S, Bennett RL, Miller M, Hall SA, Hampel H, Hisama FM, Naylor LV, Goetsch C, Leppig K, Tait JF, Scroggins SM, Turner EH, Livingston R, Salipante SJ, King MC, Walsh T, Pritchard CC.

Genet Med. 2016 Oct;18(10):974-81. doi: 10.1038/gim.2015.212. Epub 2016 Feb 4.

PubMed [citation]

PMID:: 26845104

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000186093.9

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

Description

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.

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000266231.1

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

From Color Diagnostics, LLC DBA Color Health, SCV000686608.5

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

Description

This missense variant replaces cysteine with tryptophan at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/195444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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