ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1142T>A (p.Leu381Gln)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV003224054 SCV003919687 uncertain significance not provided 2023-04-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805)
Baylor Genetics RCV003475545 SCV004203542 uncertain significance Colorectal cancer, susceptibility to, 12 2023-09-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV004285602 SCV005008944 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-09 criteria provided, single submitter clinical testing The c.1142T>A (p.L381Q) alteration is located in exon 12 (coding exon 12) of the POLE gene. This alteration results from a T to A substitution at nucleotide position 1142, causing the leucine (L) at amino acid position 381 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Centre For Genomic Medicine, NCGM RCV003475545 SCV005329342 uncertain significance Colorectal cancer, susceptibility to, 12 2023-05-20 criteria provided, single submitter clinical testing The missense c.1142T>A (p.Leu381Gln) variant in the POLE gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. The amino acid Leucine at position 381 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen -Probably damaging/Benign, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Leu381Gln in POLE is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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