ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.255G>A (p.Lys85=)

dbSNP: rs747851551
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569645 SCV000674421 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-19 criteria provided, single submitter clinical testing The c.255G>A variant (also known as p.K85K), located in coding exon 3 of the POT1 gene, results from a G to A substitution at nucleotide position 255. This nucleotide substitution does not change the at codon 85. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000820144 SCV000960842 pathogenic Tumor predisposition syndrome 3 2022-08-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 30451293; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 486150). This variant has been observed in individual(s) with melanoma (PMID: 30451293; Invitae). This variant is present in population databases (rs747851551, gnomAD 0.0009%). This sequence change affects codon 85 of the POT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POT1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.

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