ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.197A>G (p.Tyr66Cys)

gnomAD frequency: 0.00001  dbSNP: rs776085350
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000534227 SCV000655171 uncertain significance Tumor predisposition syndrome 3 2024-01-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 66 of the POT1 protein (p.Tyr66Cys). This variant is present in population databases (rs776085350, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 475069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POT1 protein function with a negative predictive value of 80%. 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 RCV002420519 SCV002723552 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-31 criteria provided, single submitter clinical testing The p.Y66C variant (also known as c.197A>G), located in coding exon 3 of the POT1 gene, results from an A to G substitution at nucleotide position 197. The tyrosine at codon 66 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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