NM_000368.5(TSC1):c.2039G>A (p.Gly680Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 3, 2024
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:: RCV002256018.4

Allele description [Variation Report for NM_000368.5(TSC1):c.2039G>A (p.Gly680Glu)]

NM_000368.5(TSC1):c.2039G>A (p.Gly680Glu)

Gene:

TSC1:TSC complex subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.13

Genomic location:

Preferred name:

NM_000368.5(TSC1):c.2039G>A (p.Gly680Glu)

HGVS:

NC_000009.12:g.132904413C>T
NG_012386.1:g.45221G>A
NM_000368.5:c.2039G>AMANE SELECT
NM_001162426.2:c.2036G>A
NM_001162427.2:c.1886G>A
NM_001362177.2:c.1676G>A
NP_000359.1:p.Gly680Glu
NP_000359.1:p.Gly680Glu
NP_001155898.1:p.Gly679Glu
NP_001155899.1:p.Gly629Glu
NP_001349106.1:p.Gly559Glu
LRG_486t1:c.2039G>A
LRG_486:g.45221G>A
LRG_486p1:p.Gly680Glu
NC_000009.11:g.135779800C>T
NM_000368.3:c.2039G>A
NM_000368.4:c.2039G>A
p.(Gly680Glu)

Protein change:

G559E

Links:

Tuberous sclerosis database (TSC1): TSC1_00128; dbSNP: rs118203623

NCBI 1000 Genomes Browser:

rs118203623

Molecular consequence:

NM_000368.5:c.2039G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001162426.2:c.2036G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001162427.2:c.1886G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001362177.2:c.1676G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; 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
SCV002530953	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (May 21, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 10363127, 9803264 Citation Link,
SCV002723029	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 3, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10363127, 9803264 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002530953

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(May 21, 2021)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002723029

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 3, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Comprehensive mutation analysis of TSC1 using two-dimensional DNA electrophoresis with DGGE.

Dabora SL, Sigalas I, Hall F, Eng C, Vijg J, Kwiatkowski DJ.

Ann Hum Genet. 1998 Nov;62(Pt 6):491-504.

PubMed [citation]

PMID:: 10363127

A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients.

Young JM, Burley MW, Jeremiah SJ, Jeganathan D, Ekong R, Osborne JP, Povey S.

Ann Hum Genet. 1998 May;62(Pt 3):203-13.

PubMed [citation]

PMID:: 9803264

Details of each submission

From Sema4, Sema4, SCV002530953.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	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 Ambry Genetics, SCV002723029.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.G680E variant (also known as c.2039G>A), located in coding exon 14 of the TSC1 gene, results from a G to A substitution at nucleotide position 2039. The glycine at codon 680 is replaced by glutamic acid, an amino acid with similar properties. This alteration, designated as DNA change G2260A (protein change: G680E), was detected with an allele frequency of 0.6% in a cohort of 79 patients satisfying established diagnostic criteria for tuberous sclerosis. The alteration is described as a non-pathogenic polymorphism by study authors (Young JM et al. Ann. Hum. Genet., 1998 May;62:203-13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 16, 2025

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