ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.265T>C (p.Tyr89His) (rs1131691746)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493487 SCV000582742 uncertain significance not provided 2017-05-04 criteria provided, single submitter clinical testing The Y89H variant in the POT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, numerous publications highlight residue Y89 as functionally important for the protein, with in vitro studies of a different missense variant at this codon, Y89C, revealing complete abolition of telomere binding by mutant POT1 (Lei et al., 2004; Gu et al., 2017; Robles-Espinoza et al., 2014). In addition, the Y89C variant was identified in four family members with cutaneous malignant melanoma, with other cancers reported in these individuals and other untested family members, and three Y89C carriers exhibited increased telomere lengths (Robles-Espinoza et al., 2014). The Y89H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y89H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position within the OB1 domain that is conserved across species (Robles-Espinoza et al., 2014). However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We currently interpret Y89H as a variant of uncertain significance.

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