Submissions for variant NM_015450.3(POT1):c.1555G>A (p.Val519Ile)

gnomAD frequency: 0.00001  dbSNP: rs776873207

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542878	SCV000655149	uncertain significance	Tumor predisposition syndrome 3	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 519 of the POT1 protein (p.Val519Ile). This variant is present in population databases (rs776873207, gnomAD 0.002%). 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: 475048). 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	RCV001012098	SCV001172512	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-26	criteria provided, single submitter	clinical testing	The p.V519I variant (also known as c.1555G>A), located in coding exon 12 of the POT1 gene, results from a G to A substitution at nucleotide position 1555. The valine at codon 519 is replaced by isoleucine, an amino acid with highly similar 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000542878	SCV002012394	uncertain significance	Tumor predisposition syndrome 3	2021-09-09	criteria provided, single submitter	clinical testing	The POT1 c.1555G>A (p.Val519Ile) change has a maximum subpopulation frequency of 0.0026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/7-124469347-C-T). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with POT1-associated conditions. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Genetic Services Laboratory, University of Chicago	RCV001821626	SCV002065182	uncertain significance	not specified	2021-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV002264956	SCV002546943	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: telomere binding similar to wildtype (Simonin-Wilmer et al., 2022); This variant is associated with the following publications: (PMID: 28393830, 36539277)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001821626	SCV004027568	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing