Submissions for variant NM_006231.4(POLE):c.1583C>T (p.Thr528Met)

gnomAD frequency: 0.00014  dbSNP: rs116263919

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657110	SCV000289260	uncertain significance	not provided	2025-02-02	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 528 of the POLE protein (p.Thr528Met). This variant is present in population databases (rs116263919, gnomAD 0.02%). This missense change has been observed in individual(s) with personal and family history of cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 240397). 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 expected to disrupt POLE protein function with a positive 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	RCV000657110	SCV000293799	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29338689, 35534704, 38773787)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236971	SCV000601983	uncertain significance	not specified	2016-11-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563355	SCV000671275	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	The p.T528M variant (also known as c.1583C>T), located in coding exon 15 of the POLE gene, results from a C to T substitution at nucleotide position 1583. The threonine at codon 528 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236971	SCV000966739	uncertain significance	not specified	2018-12-04	criteria provided, single submitter	clinical testing	The p.Thr528Met variant in POLE has not been previously reported in individuals with colorectal cancer but has been identified in 0.02% (30/128702) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported as a variant of uncertain significance in ClinVar (Variation ID 24 0397). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the clinical significance of the p.Th r528Met variant is uncertain. ACMG/AMP Criteria applied: PP3.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657110	SCV001473388	uncertain significance	not provided	2019-09-28	criteria provided, single submitter	clinical testing	The POLE c.1583C>T; p.Thr528Met variant (rs116263919), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 240397). This variant is found in the general population with an overall allele frequency of 0.01% (34/282088 alleles) in the Genome Aggregation Database. The threonine at codon 528 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time.
Genetic Services Laboratory, University of Chicago	RCV000236971	SCV002067817	uncertain significance	not specified	2019-11-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000563355	SCV002536758	likely benign	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236971	SCV004243517	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005003576	SCV005633759	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	2024-05-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737375	SCV005350111	uncertain significance	POLE-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The POLE c.1583C>T variant is predicted to result in the amino acid substitution p.Thr528Met. This variant was reported in an individual with breast cancer (Park. 2018. PubMed ID: 29338689). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar by the majority of submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/240397/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.