Submissions for variant NM_006231.4(POLE):c.1359+4C>T

gnomAD frequency: 0.00001  dbSNP: rs752118019

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766535	SCV000544231	uncertain significance	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 13 of the POLE gene. It does not directly change the encoded amino acid sequence of the POLE protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs752118019, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 405903). 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. 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.
Ambry Genetics	RCV001011159	SCV001171449	uncertain significance	Hereditary cancer-predisposing syndrome	2018-04-24	criteria provided, single submitter	clinical testing	The c.1359+4C>T intronic variant results from a C to T substitution 4 nucleotides after coding exon 13 in the POLE gene. This nucleotide position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV002248674	SCV002519043	benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
GeneDx	RCV003766535	SCV005370021	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.