Submissions for variant NM_015450.3(POT1):c.147del (p.Ile49fs)

dbSNP: rs1064794328

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485545	SCV000568855	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Observed in an individual with glioma and in another individual with multiple cancers including lymphoma, melanoma, and papillary thyroid cancer (Jones et al., 2015; Jajosky et al., 2022); This variant is associated with the following publications: (PMID: 35456397, 25877891)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692016	SCV000819821	pathogenic	Tumor predisposition syndrome 3	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile49Metfs*7) in the POT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POT1 are known to be pathogenic (PMID: 32155570). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with glioma (PMID: 25877891). ClinVar contains an entry for this variant (Variation ID: 420174). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001011800	SCV001172163	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	The c.147delT pathogenic mutation, located in coding exon 3 of the POT1 gene, results from a deletion of one nucleotide at nucleotide position 147, causing a translational frameshift with a predicted alternate stop codon (p.I49Mfs*7). This alteration has been reported in an individual diagnosed with glioma (Jones S et al. Sci Transl Med, 2015 Apr;7:283ra53). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001011800	SCV005400244	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hereditary neoplastic syndrome (MONDO#0015356), POT1-related. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMIDs: 25482530, 29693246, 33216348). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER; PMIDs: 25482530, 27528712, 34769003). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been identified as a germline variant in an individual with a history of multiple primary tumours (PMID: 35456397), an individual with glioma (PMID: 25877891); and classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
The Telomere Center at Johns Hopkins, Johns Hopkins University School of Medicine	RCV003329289	SCV003853312	pathogenic	Long telomere syndrome	2022-08-01	no assertion criteria provided	clinical testing