ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.1594G>C (p.Ala532Pro)

gnomAD frequency: 0.00003  dbSNP: rs537377921
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570928 SCV000674424 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing The c.1594G>C variant (also known as p.A532P), located in coding exon 12 of the POT1 gene, results from a G to C substitution at nucleotide position 1594. The amino acid change results in alanine to proline at codon 532, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in familial melanoma and in an individual with sporadic multiple primary melanomas (Shi J et al. Nat. Genet., 2014 May;46:482-6). Functional studies and in vitro studies in yeast cells have shown that the c.1594G>C alteration disrupts the interaction of POT1 with TPP1, causing a deregulation of telomere length (Liu J et al. Cell Rep, 2015 Sep;12:2169-80). It is important to note that the functional studies did not account for a potential splicing impact, but rather a missense mechanism of mutation. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by BDGP; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, and the mechanism of mutation is unknown, the clinical significance of this alteration remains unclear.
Invitae RCV001346858 SCV001541093 uncertain significance Tumor predisposition syndrome 3 2022-10-16 criteria provided, single submitter clinical testing 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects POT1 function (PMID: 26365187, 28393830). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 486153). This variant has been observed in individual(s) with melanoma (PMID: 24686846). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change affects codon 532 of the POT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POT1 protein. This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.