NM_198253.3(TERT):c.2110C>T (p.Pro704Ser) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000520116.13

Allele description [Variation Report for NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)]

NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)

Gene:

TERT:telomerase reverse transcriptase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_198253.3(TERT):c.2110C>T (p.Pro704Ser)

HGVS:

NC_000005.10:g.1279311G>A
NG_009265.1:g.20737C>T
NM_001193376.3:c.2110C>T
NM_198253.3:c.2110C>TMANE SELECT
NP_001180305.1:p.Pro704Ser
NP_937983.2:p.Pro704Ser
NP_937983.2:p.Pro704Ser
LRG_343t1:c.2110C>T
LRG_343:g.20737C>T
LRG_343p1:p.Pro704Ser
NC_000005.9:g.1279426G>A
NM_198253.2:c.2110C>T
NR_149162.3:n.2189C>T
NR_149163.3:n.2189C>T
O14746:p.Pro704Ser

Protein change:

P704S; PRO704SER

Links:

UniProtKB: O14746#VAR_068793; OMIM: 187270.0014; dbSNP: rs199422297

NCBI 1000 Genomes Browser:

rs199422297

Molecular consequence:

NM_001193376.3:c.2110C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198253.3:c.2110C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_149162.3:n.2189C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_149163.3:n.2189C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000617543	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 22, 2022)	germline	clinical testing	Citation Link,
SCV003840113	Genetic Services Laboratory, University of Chicago	no assertion criteria provided	Likely pathogenic (Oct 14, 2022)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617543

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 22, 2022)

germline

clinical testing

Citation Link,

SCV003840113

Genetic Services Laboratory, University of Chicago

no assertion criteria provided

Likely pathogenic
(Oct 14, 2022)

germline

clinical testing

Help

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000617543.4

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

Description

Observed in individuals with TERT-related disorders in published literature (Du 2009, Batista 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30523342, 23901009, 18042801, 18635888, 23538340, 18931339, 27418648, 21602826, 28099038)

#	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, SCV003840113.1

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

Description

The c.2110C>T sequence change in exon 5 results in an amino acid change, p.Pro704Ser. The p.Pro704Ser change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro704Ser substitution. This sequence change has been reported in the homozygous state in two individuals with dyskeratosis congenital (PMID: 18042801, 18931339). It has also been described in the heterozygous state in three individuals from one family with pulmonary fibrosis and one individual with aplastic anemia (PMID: 1863588, 18931339). Multiple studies have found that the p.Pro704Ser change results in reduced telomerase activity (PMID: 18042801, 23901009. 18931339). This sequence change has been described in the gnomAD database in 2 individuals which corresponds to a population frequency of 0.0009% (dbSNP rs199422297). Based on these evidences this sequence change is classified as likely pathogenic.

#	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

Last Updated: May 1, 2024

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