Submissions for variant NM_015450.3(POT1):c.10-2A>C

dbSNP: rs1554434788

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000541909	SCV000655114	pathogenic	Tumor predisposition syndrome 3	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the POT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of POT1-related conditions (PMID: 34193977). ClinVar contains an entry for this variant (Variation ID: 475014). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003114674	SCV003798827	likely pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with myeloproliferative neoplasm, monoclonal B cell lymphocytosis, and intradural meningioma (Lim et al., 2021); This variant is associated with the following publications: (PMID: 31937561, 34193977)
Ambry Genetics	RCV003302882	SCV004002041	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	The c.10-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 2 in the POT1 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been observed in at least one individual with a personal and family history that is consistent with POT1-related disease (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.