Submissions for variant NM_198253.3(TERT):c.1317_1319GGA[2] (p.Glu441del) (rs377639087)

Total submissions: 11

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,Partners HealthCare 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	RCV001079649	SCV000291846	likely benign	Idiopathic Pulmonary Fibrosis; Dyskeratosis congenita, autosomal dominant, 2	2019-12-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000370254	SCV000452691	likely benign	Aplastic anemia	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000275900	SCV000452692	likely benign	Dyskeratosis Congenita, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000312359	SCV000452693	likely benign	Idiopathic Pulmonary Fibrosis	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000192469	SCV000565612	likely benign	not specified	2016-12-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	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; Cutaneous malignant melanoma 9	2018-09-12	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	Idiopathic Pulmonary Fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Clinical Genomics Lab, 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.