Submissions for variant NM_198253.3(TERT):c.1936C>T (p.Arg646Cys)

gnomAD frequency: 0.00006  dbSNP: rs147521473

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518369	SCV000291854	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2025-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001775705	SCV002013744	uncertain significance	not provided	2025-02-09	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Identified as a presumed germline variant in an individual with myeloid neoplasm and observed in an individual with cirrhosis (PMID: 30964210, 35106810); This variant is associated with the following publications: (PMID: 35106810, 30964210)
Genetic Services Laboratory, University of Chicago	RCV001820780	SCV002065370	uncertain significance	not specified	2021-06-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TERT gene demonstrated a sequence change, c.1936C>T, in exon 4 that results in an amino acid change, p.Arg646Cys. This sequence change has been described in gnomAD with a frequency of 0.0077% in the Non-Finnish European sub-population (dbSNP rs147521473). The p.Arg646Cys change affects a poorly conserved amino acid residue located in a domain of the TERT protein that is \ known to be functional. The p.Arg646Cys substitution appears to be tolerated using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with TERT-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Arg646Cys change remains unknown at this time.
Sema4, Sema4	RCV002256176	SCV002533114	uncertain significance	Dyskeratosis congenita	2021-07-02	criteria provided, single submitter	curation
Baylor Genetics	RCV003469172	SCV004208100	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2023-10-18	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003469172	SCV005689333	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2024-08-23	criteria provided, single submitter	clinical testing	The TERT c.1936C>T (p.Arg646Cys) missense change has a maximum subpopulation frequency of 0.0077% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PMID: 27535533). This variant has been reported in an individual with Hodgkin lymphoma (PMID: 35106810). To our knowledge, this variant has not been reported in individuals with clinical features of dyskeratosis congenita. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004734890	SCV005350957	uncertain significance	TERT-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The TERT c.1936C>T variant is predicted to result in the amino acid substitution p.Arg646Cys. This variant has been reported in an individual with cirrhosis and in an individual with therapy-related myeloid neoplasm (Chiu et al. 2019. PubMed ID: 30964210; Gurnari et al. 2022. PubMed ID: 35106810). This variant is reported in 0.0077% of alleles in individuals of European (non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.