NM_000548.5(TSC2):c.1839+6G>A AND not specified

Germline classification:: Benign/Likely benign (5 submissions)
Last evaluated:: Nov 23, 2018
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000349195.10

Allele description [Variation Report for NM_000548.5(TSC2):c.1839+6G>A]

NM_000548.5(TSC2):c.1839+6G>A

Gene:

TSC2:TSC complex subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000548.5(TSC2):c.1839+6G>A

HGVS:

NC_000016.10:g.2070584G>A
NG_005895.1:g.26279G>A
NM_000548.5:c.1839+6G>AMANE SELECT
NM_001077183.3:c.1839+6G>A
NM_001114382.3:c.1839+6G>A
NM_001318827.2:c.1728+6G>A
NM_001318829.2:c.1692+6G>A
NM_001318831.2:c.1239+6G>A
NM_001318832.2:c.1872+6G>A
NM_001363528.2:c.1839+6G>A
NM_001370404.1:c.1839+6G>A
NM_001370405.1:c.1839+6G>A
NM_021055.3:c.1839+6G>A
LRG_487t1:c.1839+6G>A
LRG_487:g.26279G>A
NC_000016.9:g.2120585G>A
NM_000548.3:c.1839+6G>A
NM_000548.4:c.1839+6G>A
p.(=)

Links:

Tuberous sclerosis database (TSC2): TSC2_00425; dbSNP: rs45517204

NCBI 1000 Genomes Browser:

rs45517204

Molecular consequence:

NM_000548.5:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001077183.3:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001114382.3:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001318827.2:c.1728+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001318829.2:c.1692+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001318831.2:c.1239+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001318832.2:c.1872+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001363528.2:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001370404.1:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001370405.1:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_021055.3:c.1839+6G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000342015	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Jun 23, 2016)	germline	clinical testing	Citation Link,
SCV000515024	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Mar 13, 2015)	germline	clinical testing	Citation Link,
SCV000918334	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 23, 2018)	germline	clinical testing	Citation Link,
SCV001970874	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV003839165	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Likely benign (Dec 19, 2022)	germline	clinical testing

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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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Eurofins Ntd Llc (ga), SCV000342015.4

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

From GeneDx, SCV000515024.4

#	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 considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918334.1

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

Description

Variant summary: TSC2 c.1839+6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00044 in 276158 control chromosomes, predominantly at a frequency of 0.0009 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), while the overall frequency of the variant is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant; these data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1839+6G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (TSC2 c.2968_2971dupAGGA, p.Ile991Lysfs*16; TSC2 c.2590C>T, p.Gln864*) (LOVD (Tuberous sclerosis database)), providing supporting evidence for a benign role. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as 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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001970874.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV003839165.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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