Submissions for variant NM_198253.3(TERT):c.887A>C (p.His296Pro)

gnomAD frequency: 0.00007  dbSNP: rs778187343

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000378796	SCV000452700	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000283392	SCV000452701	uncertain significance	Aplastic anemia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000322037	SCV000452702	benign	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518795	SCV000551510	likely benign	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2025-01-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765804	SCV000897194	uncertain significance	Interstitial lung disease 2; Aplastic anemia; Dyskeratosis congenita, autosomal dominant 1; Acute myeloid leukemia; Dyskeratosis congenita, autosomal dominant 2; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1; Melanoma, cutaneous malignant, susceptibility to, 9	2018-10-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820800	SCV002071236	uncertain significance	not specified	2019-09-20	criteria provided, single submitter	clinical testing
GeneDx	RCV002305476	SCV002599644	uncertain significance	not provided	2023-11-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate intracellular protein synthesis similar to wild type (PMID: 28677271); Observed in an individual with hepatocellular carcinoma and in a blood sample from an individual with myelodysplastic syndrome but where germline reference tissue was unavailable for testing (PMID: 28677271, 34019641); This variant is associated with the following publications: (PMID: 28677271, 34019641)
Ambry Genetics	RCV004822030	SCV005512330	uncertain significance	Dyskeratosis congenita	2024-08-29	criteria provided, single submitter	clinical testing	The p.H296P variant (also known as c.887A>C), located in coding exon 2 of the TERT gene, results from an A to C substitution at nucleotide position 887. The histidine at codon 296 is replaced by proline, an amino acid with similar properties. This variant was reported in an individual with features consistent with TERT-related disorder (Reilly CR et al. Blood, 2021 Sep;138:898-911). Functional studies suggest this variant may reduce telomere elongation capacity; however, the physiological relevance of this finding is unclear (Reilly CR et al. Blood, 2021 Sep;138:898-911). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Metabolic Liver Diseases Lab, Fondazione IRCCS Ca Granda Policlinico, University of Milan	RCV000503276	SCV000328547	uncertain significance	Hepatocellular carcinoma	2016-06-01	no assertion criteria provided	case-control