Submissions for variant NM_198253.3(TERT):c.2141C>T (p.Thr714Met)

gnomAD frequency: 0.00005  dbSNP: rs772441504

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525587	SCV000551536	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2025-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559084	SCV002729268	uncertain significance	Dyskeratosis congenita	2016-11-22	criteria provided, single submitter	clinical testing	The p.T714M variant (also known as c.2141C>T), located in coding exon 6 of the TERT gene, results from a C to T substitution at nucleotide position 2141. The threonine at codon 714 is replaced by methionine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is poorly conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150818	SCV003839116	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2022-12-06	criteria provided, single submitter	clinical testing	This TERT missense variant (rs772441504) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 20/282726 total alleles; 0.0071%; no homozygotes). c.2141C>T in TERT has been reported in ClinVar (Variation ID 410687), but not in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated and while the threonine residue at this position is evolutionarily conserved across many of species assessed, several species have a different amino acid at this position, including methionine. We consider the clinical significance of c.2141C>T; p.Thr714Met in TERT to be uncertain at this time.
Johns Hopkins Genomics, Johns Hopkins University	RCV003150819	SCV003839117	uncertain significance	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2022-12-06	criteria provided, single submitter	clinical testing	This TERT missense variant (rs772441504) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 20/282726 total alleles; 0.0071%; no homozygotes). c.2141C>T in TERT has been reported in ClinVar (Variation ID 410687), but not in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated and while the threonine residue at this position is evolutionarily conserved across many of species assessed, several species have a different amino acid at this position, including methionine. We consider the clinical significance of c.2141C>T; p.Thr714Met in TERT to be uncertain at this time.
GeneDx	RCV003233642	SCV003930773	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27149842)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003150818	SCV005689334	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2025-02-05	criteria provided, single submitter	clinical testing	The TERT c.2141C>T (p.Thr714Met) missense change has a maximum subpopulation frequency of 0.02% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has not been reported in individuals with dyskeratosis congenita. In summary, the evidence currently available is insufficient to determine the role of this variant in dyskeratosis congenita. It has therefore been classified as of uncertain significance.