ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4307G>A (p.Arg1436Gln)

gnomAD frequency: 0.00004  dbSNP: rs754518522
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000985979 SCV000653283 uncertain significance not provided 2024-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1436 of the POLE protein (p.Arg1436Gln). This variant is present in population databases (rs754518522, 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: 473660). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985979 SCV001134728 uncertain significance not provided 2019-04-18 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000544678 SCV001775503 uncertain significance Colorectal cancer, susceptibility to, 12 2021-07-29 criteria provided, single submitter clinical testing The POLE c.4307G>A (p.Arg1436Gln) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133220130-C-T). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with a personal history of breast cancer diagnosed at age 48 and a family history of stomach and colon cancers (PMID: 32522261). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3.
GeneDx RCV000985979 SCV001793081 uncertain significance not provided 2024-07-10 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer, as well as in her unaffected brother (PMID: 32522261); This variant is associated with the following publications: (PMID: 28481359, 32522261)
Mendelics RCV003492097 SCV004232583 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV004943999 SCV005478816 uncertain significance Hereditary cancer-predisposing syndrome 2024-08-29 criteria provided, single submitter clinical testing The p.R1436Q variant (also known as c.4307G>A), located in coding exon 34 of the POLE gene, results from a G to A substitution at nucleotide position 4307. The arginine at codon 1436 is replaced by glutamine, an amino acid with highly similar properties. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005010516 SCV005633699 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 2024-01-19 criteria provided, single submitter clinical testing

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