Submissions for variant NM_006231.4(POLE):c.4522C>G (p.Arg1508Gly)

dbSNP: rs766511597

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000759299	SCV000653296	uncertain significance	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1508 of the POLE protein (p.Arg1508Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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: 473670). 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.
Mendelics	RCV000709255	SCV000838686	uncertain significance	Familial colorectal cancer	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759299	SCV000888544	uncertain significance	not provided	2019-02-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765053	SCV000896250	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000759299	SCV001795314	uncertain significance	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified via exome sequencing in an individual with common variable immunodeficiency for whom no information about personal or family cancer history was provided (Maffucci et al., 2016); This variant is associated with the following publications: (PMID: 27379089)
PreventionGenetics, part of Exact Sciences	RCV003419986	SCV004116695	uncertain significance	POLE-related condition	2022-09-15	criteria provided, single submitter	clinical testing	The POLE c.4522C>G variant is predicted to result in the amino acid substitution p.Arg1508Gly. This variant has been reported in an individual with immunodeficiency (Maffucci et al. 2016. Pubmed ID:27379089, Supplementary table 5). Different variant at the same codon p.Arg1508His was reported in hereditary cancer predisposition as variant of unknown significance (Velázquez et al. 2020. Pubmed ID:32522261, Table S1). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133219839-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987601	SCV004804449	uncertain significance	not specified	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: POLE c.4522C>G (p.Arg1508Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4522C>G has been reported in the literature in an individual affected with immunodeficiency (Maffucci_2016). This report does not provide unequivocal conclusions about association of the variant with Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27379089). ClinVar contains an entry for this variant (Variation ID: 473670). Based on the evidence outlined above, the variant was classified as uncertain significance.