ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.1810G>A (p.Glu604Lys)

gnomAD frequency: 0.00003  dbSNP: rs753762757
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519301 SCV000617700 uncertain significance not provided 2022-10-13 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28393830)
Invitae RCV000652225 SCV000774093 uncertain significance Tumor predisposition syndrome 3 2024-01-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 604 of the POT1 protein (p.Glu604Lys). This variant is present in population databases (rs753762757, gnomAD 0.005%). 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: 449494). 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 RCV001013210 SCV001173763 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-03 criteria provided, single submitter clinical testing The p.E604K variant (also known as c.1810G>A), located in coding exon 15 of the POT1 gene, results from a G to A substitution at nucleotide position 1810. The glutamic acid at codon 604 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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 RCV000652225 SCV004171514 uncertain significance Tumor predisposition syndrome 3 2023-10-25 criteria provided, single submitter clinical testing The POT1 c.1810G>A (p.Glu604Lys) missense change has a maximum subpopulation frequency of 0.0045% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with melanoma (PMID: 36539277). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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