ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3311C>T (p.Thr1104Met)

gnomAD frequency: 0.00007  dbSNP: rs531705054
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000483749 SCV000544127 uncertain significance not provided 2025-01-30 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 1104 of the POLE protein (p.Thr1104Met). This variant is present in population databases (rs531705054, gnomAD 0.02%). 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: 405803). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative predictive value of 80%. 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 RCV000483749 SCV000572235 uncertain significance not provided 2024-02-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a colorectal cancer patients (PMID: 37965459); This variant is associated with the following publications: (PMID: 23528559, 25228659, 37965459)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192843 SCV001361234 uncertain significance not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: POLE c.3311C>T (p.Thr1104Met) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 277216 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3311C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Baylor Genetics RCV001293921 SCV001482617 uncertain significance Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2020-12-01 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000468457 SCV002032299 uncertain significance Colorectal cancer, susceptibility to, 12 2021-12-01 criteria provided, single submitter clinical testing The POLE c.3311C>T (p.Thr1104Met) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133234521-G-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. This variant has been identified in hypermutated tumors (PMID: 29056344), as well as those with low tumor mutational burden (PMID: 29056344). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Genetic Services Laboratory, University of Chicago RCV001192843 SCV002072344 uncertain significance not specified 2019-04-05 criteria provided, single submitter clinical testing

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