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

gnomAD frequency: 0.00004  dbSNP: rs199422297

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520116	SCV000617543	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing	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)
Invitae	RCV003103717	SCV000650730	likely pathogenic	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 704 of the TERT protein (p.Pro704Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of TERT-related conditions (PMID: 18042801, 18635888, 18931339, 21602826, 27418648, 30523342; Invitae). ClinVar contains an entry for this variant (Variation ID: 39108). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects TERT function (PMID: 18042801, 21602826, 23901009, 25365545). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002415443	SCV002726983	pathogenic	Dyskeratosis congenita; Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	The p.P704S pathogenic mutation (also known as c.2110C>T), located in coding exon 5 of the TERT gene, results from a C to T substitution at nucleotide position 2110. The proline at codon 704 is replaced by serine, an amino acid with similar properties. This mutation has demonstrated both an autosomal recessive inheritance presenting with a more severe phenotype as well as autosomal dominant inheritance with variable presentation, age of onset, and reduced penetrance. This alteration was first reported in homozygous state in a proband diagnosed with dyskeratosis congenita and additional abnormalities; one parent who was compound heterozygous with another alteration had shortened telomeres, while the other heterozygous parent was asymptomatic in the 6th decade of life. Functional analysis in this study demonstrated that this mutation severely reduced telomerase activity to 13% of wild type (Du HY et al. Blood, 2008 Feb;111:1128-30). This mutation was also identified in the heterozygous state in three siblings with pulmonary fibrosis, and other unrelated individuals with myelodysplastic syndrome and/or pulmonary fibrosis (Cronkhite JT et al. Am. J. Respir. Crit. Care Med., 2008 Oct;178:729-37; Keel SB et al. Haematologica, 2016 11;101:1343-1350; Gutierrez-Rodrigues F et al. Genet Med, 2019 07;21:1594-1602). Additional in vitro functional studies demonstrated that this mutation significantly reduces activity and processivity of telomerase (Batista LF et al. Nature, 2011 Jun;474:399-402; Zaug AJ et al. Nucleic Acids Res., 2013 Oct;41:8969-78). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003460537	SCV004208116	pathogenic	Dyskeratosis congenita, autosomal dominant 2	2023-09-27	criteria provided, single submitter	clinical testing
OMIM	RCV000022786	SCV000044075	pathogenic	Autosomal recessive dyskeratosis congenita 4	2008-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000032375	SCV000056031	not provided	Dyskeratosis congenita, autosomal dominant 1		no assertion provided	literature only
Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center	RCV002509175	SCV002547403	likely risk allele	Pulmonary fibrosis	2022-06-09	no assertion criteria provided	research	Leukocyte telomere length (by qPCR) less than 10th percentile age-adjusted
Genetic Services Laboratory, University of Chicago	RCV000520116	SCV003840113	likely pathogenic	not provided	2022-10-14	no assertion criteria provided	clinical testing	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.