Submissions for variant NM_015450.3(POT1):c.1851_1852del (p.Asp617fs)

dbSNP: rs758673417

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535739	SCV000655168	uncertain significance	Tumor predisposition syndrome 3	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp617Glufs*9) in the POT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the POT1 protein. This variant is present in population databases (rs758673417, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with acute myeloid leukemia, colorectal cancer, head and neck squamous cell carcinoma, oligodendroglioma, and/or uveal and cutaneous melanoma (PMID: 25482530, 27329137, 29625052, 32191290, 32907878, 34193977). This variant is also known as c.1458_1459del. ClinVar contains an entry for this variant (Variation ID: 209095). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001013390	SCV001173969	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-26	criteria provided, single submitter	clinical testing	The c.1851_1852delTA variant, located in coding exon 15 of the POT1 gene, results from a deletion of two nucleotides at nucleotide positions 1851 to 1852, causing a translational frameshift with a predicted alternate stop codon (p.D617Efs*9). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of POT1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 18 amino acids of the protein. Another alteration, Q623H, located downstream of this frameshift was identified in a familial melanoma case, and has been shown to be important for binding to TPP1 and proper telomere maintenance (Shi J et al. Nat. Genet. 2014 May;46:482-6; Rice C et al. Nat. Commun. 2017 Apr;8:14928). Additionally, internal case control analysis showed a significant association of melanoma and sarcoma in probands heterozygous for c.1851_1852delTA compared to probands with a negative multigene testing panel result (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV001753590	SCV001986361	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation as the last 18 amino acids are replaced with 8 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 27329137, 25710457, 25482530, 26847028, 32449991, 28393830, 34193977, 29625052, 32987645, 32907878)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000535739	SCV002584581	uncertain significance	Tumor predisposition syndrome 3	2022-08-26	criteria provided, single submitter	clinical testing	The POT1 c.1851_1852del (p.Asp617GlufsTer9) change deletes two nucleotides and causes a frameshift and the creation of a premature stop codon. It is not expected to result in nonsense mediated decay and removes less than 10% of the protein. Functional studies have demonstrated the importance of the C-terminus of POT1 in protein-protein interactions, however studies are needed to determine the effect of this variant (PMID: 28393832; 28393830). This variant has been reported in an individual with a personal and family history of oligodendroglioma (PMID: 25482530) and in an individual with uveal melanoma (PMID: 32907878). This variant has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). 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.
OMIM	RCV000535739	SCV000246014	pathogenic	Tumor predisposition syndrome 3	2014-12-07	no assertion criteria provided	literature only