Submissions for variant NM_006231.4(POLE):c.6136G>A (p.Gly2046Arg)

dbSNP: rs1462887616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000760030	SCV000772645	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2046 of the POLE protein (p.Gly2046Arg). This variant also falls at the last nucleotide of exon 44, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 540694). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	RCV000760030	SCV000889780	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768286	SCV000898890	uncertain significance	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2017-10-19	criteria provided, single submitter	clinical testing	POLE NM_006231.3 exon 44 p.Gly2046Arg (c.6136G>A): This variant has not been reported in the literature but is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs not available). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000760030	SCV002538732	uncertain significance	not provided	2022-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Revvity Omics, Revvity	RCV000760030	SCV003809193	uncertain significance	not provided	2022-06-14	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224368	SCV003920339	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	2021-03-30	criteria provided, single submitter	clinical testing	POLE NM_006231 exon 44 p.Gly2046Arg (c.6136G>A): This variant has not been reported in the literature but is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs not available). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.