ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.907C>T (p.Gln303Ter)

gnomAD frequency: 0.00001  dbSNP: rs749117997
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003655124 SCV000653491 pathogenic not provided 2023-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln303*) in the POLE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POLE are known to be pathogenic (PMID: 23230001, 25948378, 30503519). This variant is present in population databases (rs749117997, gnomAD 0.01%). 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: 473841). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001018801 SCV001180080 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-13 criteria provided, single submitter clinical testing The p.Q303* variant (also known as c.907C>T), located in coding exon 9 of the POLE gene, results from a C to T substitution at nucleotide position 907. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function via haploinsufficiency in POLE has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003655124 SCV005080458 likely pathogenic not provided 2023-06-06 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with endometrial cancer (Huang et al., 2018); This variant is associated with the following publications: (PMID: 29625052, 25948378, 23230001, 30503519)
Fulgent Genetics, Fulgent Genetics RCV005010520 SCV005633766 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 2024-04-25 criteria provided, single submitter clinical testing

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