Submissions for variant NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)

dbSNP: rs377639087

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192469	SCV000249151	likely benign	not specified	2015-03-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000192469	SCV000272498	likely benign	not specified	2018-03-22	criteria provided, single submitter	clinical testing	p.Glu441del in exon 2 of TERT: This variant is classified as likely benign becau se it has been identified in 0.4% (248/68934) of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs3776 39087). Of note, gibbons have a deletion at this position despite high nearby am ino acid conservation. In addition, although this variant has been reported in s everal studies in individuals with TERT-related conditions, many of these studie s consider the variant to be a polymorphism and the functional evidence availabl e suggests this variant does not have a significant impact on telomere length (Y amaguchi 2005, Calado 2009, Calado 2011, Kirwan 2009, Calado 2011, Fernandez 201 2, Zaug 2013, Maxwell 2016). ACMG/AMP Criteria applied: BS1; BS3_Supporting.
Invitae	RCV002517983	SCV000291846	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000370254	SCV000452691	likely benign	Aplastic anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275900	SCV000452692	likely benign	Dyskeratosis Congenita, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000312359	SCV000452693	likely benign	Interstitial lung disease 2	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000726693	SCV000565612	likely benign	not provided	2020-12-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27153395, 22853774, 21520173, 23901009, 19147845, 19674077, 19760749, 15814878, 28951115)
Eurofins Ntd Llc (ga)	RCV000726693	SCV000702135	uncertain significance	not provided	2016-10-26	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768107	SCV000899022	uncertain significance	Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant 2; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1; Melanoma, cutaneous malignant, susceptibility to, 9	2021-03-30	criteria provided, single submitter	clinical testing	TERT NM_198253.2 exon 2 p.Glu441del (c.1323_1325del): This variant has been reported in the literature as heterozygous in at 2 least individuals with varying phenotypes (hepatic cirrhosis, aplastic anemia) as well as homozygous in 1 individual with acute myelogenous leukemia (AML) (Yamaguchi 2005 PMID:15814878, Calado 2009 PMID:19674077, Calado 2009 PMID:19147845, Calado 2011 PMIDL21520173). The interpretation of this variant in the current literature is unclear, with at least 2 publications calling this variant a polymorphism (Yamaguchi 2005 PMID:15814878, Maxwell 2016 PMID:27153395). Functional studies are also conflicting, suggesting either a 40% reduction (compared to WT) to near normal effect of this variant on telomerase enzyme activity (Calado 2009 PMID:19147845, Zaug 2013 PMID:23901009). This variant is also present in 0.3% (248/68934) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/5-1293675-GTCC-G). This variant is present in ClinVar, with discrepant classifications ranging from likely benign to variant of uncertain significance (Variation ID:212398).This variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acids. This is not predicted to alter the reading frame, but the ultimate effect of this variant on the protein is unclear. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mendelics	RCV000312359	SCV001136806	benign	Interstitial lung disease 2	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001261857	SCV001439199	likely benign	Dyskeratosis congenita	2020-09-10	criteria provided, single submitter	clinical testing	The p.Glu441del frameshift variant has a frequency of 0.001719 (311 of 180,940 alleles) in gnomAD v2.1.1 with a maximal allele frequency of 0.003621 (261 of 72,072) in the European non-Finnish subpopulation (http://gnomad.broadinstitute.org). Pathogenic variants in the TERT gene predispose individuals to dyskeratosis congenita (DKC). While the exact prevalence of DKC is unknown, it is estimated to occur in approximately 1 in 1 million people. Therefore, the population frequency is not consistent with disease (BS1). This variant has been reported as heterozygous in an individual with aplastic anemia (PMID: 19674077) and as homozygous in an individual with acute myeloid leukemia (PMID: 19147845). The variant represents an in-frame deletion of 1 glutamic acid residue in a repeat of 3 glutamic acid residues (BP3). Results of telomerase activity assays have been conflicting. In several reports, the E441del variant has similar activity to the wild-type allele (PMID: 15814878, 23901009), however another report demonstrated approximately 40% of functional activity as compared to the wild-type allele (PMID: 19147845). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP3.
CeGaT Center for Human Genetics Tuebingen	RCV000726693	SCV001748114	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	TERT: BP3, BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000726693	SCV002010201	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001261857	SCV002533101	likely benign	Dyskeratosis congenita	2021-05-18	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004530148	SCV004734438	likely benign	TERT-related disorder	2023-06-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726693	SCV001554358	likely benign	not provided		no assertion criteria provided	clinical testing	The TERT p.Glu441del variant was identified in the literature in two patients with aplastic anemia, a patient with acute myeloid leukemia and another patient with cirrhosis caused by alcohol (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19674077; Calado_2009_PMID:19147845; Calado_2011_PMID:21520173). The variant was identified in dbSNP (ID: rs377639087), Cosmic, LOVD 3.0 and ClinVar (classified as likely benign by GeneDx, Invitae, Laboratory for Molecular Medicine, Illumina and Genetic Services Laboratory, University of Chicago and as uncertain significance by EGL Genetics and Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago). The variant was identified in control databases in 311 of 180940 chromosomes at a frequency of 0.001719 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 261 of 72072 chromosomes (freq: 0.003621), Other in 14 of 5334 chromosomes (freq: 0.002625), Ashkenazi Jewish in 9 of 8490 chromosomes (freq: 0.00106), European (Finnish) in 10 of 18616 chromosomes (freq: 0.000537), Latino in 11 of 25422 chromosomes (freq: 0.000433), African in 5 of 15812 chromosomes (freq: 0.000316) and South Asian in 1 of 22778 chromosomes (freq: 0.000044), but was not observed in the East Asian population. This variant is an in-frame deletion resulting in the removal of a glutamic acid (glu) residue at codon 441; the impact of this alteration on TERT protein function is not known. Functional studies have shown no association with telomere shortening but a decrease in telomere activity has been reported (Yamaguchi_2005_PMID:15814878; Calado_2009_PMID:19147845). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Molecular Oncology - Human Genetics Lab, University of Sao Paulo	RCV001843492	SCV002103148	pathogenic	Hepatoblastoma		no assertion criteria provided	research