ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6408C>T (p.Gly2136=)

gnomAD frequency: 0.00003  dbSNP: rs1057524549
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679661 SCV000535869 uncertain significance not provided 2024-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV000679661 SCV000544058 likely benign not provided 2024-10-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563555 SCV000671395 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-29 criteria provided, single submitter clinical testing The c.6408C>T variant (also known as p.G2136G), located in coding exon 46, results from a C to T substitution at nucleotide position 6408 of the POLE gene. This nucleotide substitution does not change the amino acid at codon 2136. This nucleotide position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV000679661 SCV000806833 uncertain significance not provided 2017-11-30 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000467847 SCV002012412 uncertain significance Colorectal cancer, susceptibility to, 12 2021-08-10 criteria provided, single submitter clinical testing The POLE c.6408C>T (p.Gly2136=) synonymous change has a maximum subpopulation frequency of 0.0033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133202826-G-A). Algorithms that predict the impact of sequence changes on splicing indicate that this change may create or activate a cryptic donor splice site, but RNA studies indicate no splicing effect (BS3_supporting; internal data). To our knowledge, this variant has not been reported in individuals with POLE-related disorders. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS3_supporting.

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