Submissions for variant NM_006231.4(POLE):c.6073G>A (p.Val2025Met)

gnomAD frequency: 0.00001  dbSNP: rs995579204

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000985989	SCV000543945	uncertain significance	not provided	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2025 of the POLE protein (p.Val2025Met). This variant is present in population databases (no rsID available, gnomAD 0.005%). 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: 405634). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000985989	SCV001134746	uncertain significance	not provided	2018-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000985989	SCV001777597	uncertain significance	not provided	2023-07-05	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; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 31829442)
Genetic Services Laboratory, University of Chicago	RCV001821239	SCV002071316	uncertain significance	not specified	2019-10-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001821239	SCV002550041	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002481393	SCV002779703	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
Ambry Genetics	RCV003168743	SCV003895228	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.V2025M variant (also known as c.6073G>A), located in coding exon 44 of the POLE gene, results from a G to A substitution at nucleotide position 6073. The valine at codon 2025 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004533153	SCV004117919	uncertain significance	POLE-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The POLE c.6073G>A variant is predicted to result in the amino acid substitution p.Val2025Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/405634/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.