Submissions for variant NM_006231.4(POLE):c.4582G>A (p.Ala1528Thr)

gnomAD frequency: 0.00004  dbSNP: rs373468985

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454799	SCV000540091	uncertain significance	not specified	2016-10-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is present in ExAC at a MaxMAF of 0.003%. This AA is not conserved - 30 species have a Thr at this position, including 15 mammals. It is not present in ClinVar and is predicted to be benign by multiple prediction tools.
Invitae	RCV000985981	SCV000544050	uncertain significance	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1528 of the POLE protein (p.Ala1528Thr). This variant is present in population databases (rs373468985, gnomAD 0.004%). 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: 403333). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985981	SCV001134730	uncertain significance	not provided	2018-11-21	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000471232	SCV001775526	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-08-05	criteria provided, single submitter	clinical testing	The POLE c.4582G>A (p.Ala1528Thr) missense change has a maximum subpopulation frequency of 0.0033% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133219552-C-T). Seven 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 the literature in individuals with POLE-related disease. This variant has been identified in hypermutated tumors (PMID: 29056344, 33692861), as well as those with low tumor mutational burden (PMID: 29056344). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
GeneDx	RCV000985981	SCV001785592	uncertain significance	not provided	2023-10-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in unaffected controls from a melanoma study (PMID: 29641532); This variant is associated with the following publications: (PMID: 33692861, 29056344, 36853785, 29641532)
Genetic Services Laboratory, University of Chicago	RCV000454799	SCV002071875	uncertain significance	not specified	2021-09-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POLE gene demonstrated a sequence change, c.4582G>A, in exon 36 that results in an amino acid change, p.Ala1528Thr. This sequence change has been described in the gnomAD database with a frequency of 0.003% in the non-Finnish European subpopulation (dbSNP rs373468985). The p.Ala1528Thr change affects a poorly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Ala1528Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with POLE-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala1528Thr change remains unknown at this time.
MGZ Medical Genetics Center	RCV000471232	SCV002579225	uncertain significance	Colorectal cancer, susceptibility to, 12	2021-09-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002506087	SCV002815695	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	2022-02-14	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000664293	SCV000788180	uncertain significance	Hereditary cancer-predisposing syndrome	2018-01-25	no assertion criteria provided	clinical testing