Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001045172 | SCV001209009 | uncertain significance | Tumor predisposition syndrome 3 | 2019-11-26 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 251 of the POT1 protein (p.Met251Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant has not been reported in the literature in individuals with POT1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. |
Ambry Genetics | RCV003353123 | SCV004053680 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-27 | criteria provided, single submitter | clinical testing | The p.M251I variant (also known as c.753G>A), located in coding exon 6 of the POT1 gene, results from a G to A substitution at nucleotide position 753. The methionine at codon 251 is replaced by isoleucine, an amino acid with highly similar properties. This variant was described as a germline finding in 1/3323 consecutive patients who had clinical testing for variants associated with hematologic malignancies (Lim TL et al. Leukemia, 2022 Jan;36:283-287). This amino acid position is poorly 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. |