Submissions for variant NM_006231.4(POLE):c.6730C>T (p.Leu2244Phe)

gnomAD frequency: 0.00010  dbSNP: rs375741031

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000657044	SCV000289480	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2244 of the POLE protein (p.Leu2244Phe). This variant is present in population databases (rs375741031, 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: 240616). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	RCV000657044	SCV000322141	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in both cases and controls in an ovarian cancer study (Song et al., 2021); This variant is associated with the following publications: (PMID: 23292937, 19296856, 32546565)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000255330	SCV000712557	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	The p.Leu2244Phe variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 11/66236 of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375741031). Computational prediction tools and conservation analysis sug gest that this variant may not impact the protein, though this information is no t predictive enough to rule out pathogenicity. In summary, the clinical signific ance of the p.Leu2244Phe variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657044	SCV000888574	uncertain significance	not provided	2017-12-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002479921	SCV000894722	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	2021-11-10	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000233704	SCV002032286	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-11-11	criteria provided, single submitter	clinical testing	The POLE c.6730C>T (p.Leu2244Phe) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133201508-G-A?dataset=gnomad_r2_1). 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 in individuals with POLE-related disease, tumors exhibiting microsatellite instability (MSI-H), or tumors with a high mutational burden. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000255330	SCV004027278	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000233704	SCV004228780	not provided	Colorectal cancer, susceptibility to, 12		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-20-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.