Submissions for variant NM_015450.3(POT1):c.1805G>T (p.Trp602Leu)

dbSNP: rs996577534

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001969512	SCV002260517	uncertain significance	Tumor predisposition syndrome 3	2024-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 602 of the POT1 protein (p.Trp602Leu). This variant is not present in population databases (gnomAD no frequency). 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: 1473350). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Sema4, Sema4	RCV002258348	SCV002527159	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-27	criteria provided, single submitter	curation
Ambry Genetics	RCV002258348	SCV002710849	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.W602L variant (also known as c.1805G>T), located in coding exon 15 of the POT1 gene, results from a G to T substitution at nucleotide position 1805. The tryptophan at codon 602 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002479630	SCV002774706	uncertain significance	not provided	2024-10-16	criteria provided, single submitter	clinical testing	The POT1 c.1805G>T (p.Trp602Leu) variant has not been reported in individuals with POT1-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV002479630	SCV005326706	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28393830)