ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5312C>T (p.Thr1771Met)

gnomAD frequency: 0.00001  dbSNP: rs777695766
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000484710 SCV000543906 uncertain significance not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1771 of the POLE protein (p.Thr1771Met). This variant is present in population databases (rs777695766, gnomAD 0.006%). 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: 405600). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx RCV000484710 SCV000569888 uncertain significance not provided 2020-09-09 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (Song 2020); This variant is associated with the following publications: (PMID: 31034466, 32546565)
Mendelics RCV000709250 SCV000838681 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484710 SCV001469883 uncertain significance not provided 2019-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002526396 SCV003745309 uncertain significance Inborn genetic diseases 2021-12-17 criteria provided, single submitter clinical testing The c.5312C>T (p.T1771M) alteration is located in exon 39 (coding exon 39) of the POLE gene. This alteration results from a C to T substitution at nucleotide position 5312, causing the threonine (T) at amino acid position 1771 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV003418159 SCV004117739 uncertain significance POLE-related condition 2023-09-08 criteria provided, single submitter clinical testing The POLE c.5312C>T variant is predicted to result in the amino acid substitution p.Thr1771Met. It has been reported in a case and 3 controls from an ovarian cancer cohort study (Table S6, Song et al. 2021. PubMed ID: 32546565). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133218299-G-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405600/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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