ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.281_282del (p.Gln94fs)

dbSNP: rs1397398300
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657510 SCV000779246 likely pathogenic not provided 2020-05-22 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 at a significant frequency in large population cohorts (Lek 2016); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001220394 SCV001392382 pathogenic Tumor predisposition syndrome 3 2023-03-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 545902). This variant has not been reported in the literature in individuals affected with POT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gln94Argfs*13) 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).
Ambry Genetics RCV004026009 SCV005026961 pathogenic Hereditary cancer-predisposing syndrome 2023-12-27 criteria provided, single submitter clinical testing The c.281_282delAG pathogenic mutation, located in coding exon 4 of the POT1 gene, results from a deletion of two nucleotides at nucleotide positions 281 to 282, causing a translational frameshift with a predicted alternate stop codon (p.Q94Rfs*13). This variant (designated as c.281_282del) was identified in a patient with uveal melanoma at age 57 and two primary cutaneous melanomas at ages 65 and 68; telomere length in this individual was longer than the 95th percentile of age-matched controls (Nathan V et al. J Med Genet, 2021 Apr;58:234-236). 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.

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