NM_000455.5(STK11):c.1027G>A (p.Asp343Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 11, 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:: RCV000129286.20

Allele description [Variation Report for NM_000455.5(STK11):c.1027G>A (p.Asp343Asn)]

NM_000455.5(STK11):c.1027G>A (p.Asp343Asn)

Genes:

LOC130062899:ATAC-STARR-seq lymphoblastoid active region 13597 [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.1027G>A (p.Asp343Asn)

Other names:

p.D343N:GAC>AAC

HGVS:

NC_000019.10:g.1223091G>A
NG_007460.2:g.38685G>A
NM_000455.5:c.1027G>AMANE SELECT
NP_000446.1:p.Asp343Asn
NP_000446.1:p.Asp343Asn
LRG_319t1:c.1027G>A
LRG_319:g.38685G>A
LRG_319p1:p.Asp343Asn
NC_000019.9:g.1223090G>A
NM_000455.4:c.1027G>A
p.D343N

Protein change:

D343N

Links:

dbSNP: rs368547224

NCBI 1000 Genomes Browser:

rs368547224

Molecular consequence:

NM_000455.5:c.1027G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000184047	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (May 20, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26580448, 30287823, 30883245, 33471991 Citation Link,
SCV000537536	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 11, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25742471, 26580448, 31214711, 33471991, 25741868
SCV000788215	True Health Diagnostics	no assertion criteria provided	Uncertain significance (Jan 12, 2018)	germline	clinical testing
SCV002531620	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jun 28, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance.

Abe T, Blackford AL, Tamura K, Ford M, McCormick P, Chuidian M, Almario JA, Borges M, Lennon AM, Shin EJ, Klein AP, Hruban RH, Canto MI, Goggins M.

J Clin Oncol. 2019 May 1;37(13):1070-1080. doi: 10.1200/JCO.18.01512. Epub 2019 Mar 18.

PubMed [citation]

PMID:: 30883245
PMCID:: PMC6494358

Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients.

Wong SQ, Fellowes A, Doig K, Ellul J, Bosma TJ, Irwin D, Vedururu R, Tan AY, Weiss J, Chan KS, Lucas M, Thomas DM, Dobrovic A, Parisot JP, Fox SB.

Br J Cancer. 2015 Apr 14;112(8):1411-20. doi: 10.1038/bjc.2015.80. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25742471
PMCID:: PMC4402458

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000184047.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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 Color Diagnostics, LLC DBA Color Health, SCV000537536.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces aspartic acid with asparagine at codon 343 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with an unspecified cancer (PMID: 25742471), pediatric medulloblastoma (PMID: 26580448), prostate cancer (PMID: 31214711), and breast cancer (PMID: 31214711, 33471991), but also in unaffected controls (PMID: 33471991). This variant has also been reported in four individuals age 70 years or older without cancer (FLOSSIES database; https://whi.color.com/variant/19-1223090-G-A). This variant has been identified in 5/242452 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

From True Health Diagnostics, SCV000788215.1

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

#	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 Sema4, Sema4, SCV002531620.1

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

Last Updated: Oct 20, 2024

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