Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000128420 | SCV000820615 | uncertain significance | Tumor predisposition syndrome 3 | 2021-06-11 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 89 of the POT1 protein (p.Tyr89Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant has been observed to segregate with cutaneous malignant melanoma in a family (PMID: 24686849). ClinVar contains an entry for this variant (Variation ID: 139520). 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change disrupts POT1 protein function (PMID: 24686849, 27869160). |
| Ambry Genetics | RCV002426692 | SCV002741288 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-14 | criteria provided, single submitter | clinical testing | The p.Y89C variant (also known as c.266A>G), located in coding exon 4 of the POT1 gene, results from an A to G substitution at nucleotide position 266. The tyrosine at codon 89 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in a family with cutaneous malignant melanoma and was shown to segregate with disease (Robles-Espinoza CD et al. Nat. Genet., 2014 May;46:478-481). Functional studies have indicated that the p.Y89C variant is deficient at telomere binding (Gu P et al. Oncogene, 2017 04;36:1939-1951, Robles-Espinoza CD et al. Nat. Genet., 2014 May;46:478-481), and is correlated with longer telomeres in affected individuals (Robles-Espinoza CD et al. Nat. Genet., 2014 May;46:478-481). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on internal structural analysis, Y89C changes DNA binding (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| OMIM | RCV000128420 | SCV000172098 | pathogenic | Tumor predisposition syndrome 3 | 2014-05-01 | no assertion criteria provided | literature only |