ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.94C>T (p.Leu32Phe)

gnomAD frequency: 0.00001  dbSNP: rs781513537
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001281043 SCV000289499 likely benign not provided 2025-01-12 criteria provided, single submitter clinical testing
GeneDx RCV001281043 SCV001872956 uncertain significance not provided 2024-12-04 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV003165639 SCV003899323 likely benign Hereditary cancer-predisposing syndrome 2022-12-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224235 SCV003920341 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2021-03-30 criteria provided, single submitter clinical testing POLE NM_006231.3 exon 2 p.Leu32Phe (c.94C>T): This variant has not been reported in the literature but is present in 0.07% (28/35438) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-133257834-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:240634). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV004786621 SCV005402250 uncertain significance Colorectal cancer, susceptibility to, 12 2024-05-07 criteria provided, single submitter clinical testing The POLE c.94C>T (p.Leu32Phe) missense change has a maximum subpopulation frequency of 0.08% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported as pathogenic in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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