Submissions for variant NM_006231.4(POLE):c.4759G>A (p.Val1587Ile)

gnomAD frequency: 0.00002  dbSNP: rs372388555

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001564811	SCV000653321	uncertain significance	not provided	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1587 of the POLE protein (p.Val1587Ile). This variant is present in population databases (rs372388555, gnomAD 0.02%). 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: 473692). 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 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.
Fulgent Genetics, Fulgent Genetics	RCV000765051	SCV000896248	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001564811	SCV001788031	uncertain significance	not provided	2023-10-23	criteria provided, single submitter	clinical testing	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
Ambry Genetics	RCV004024247	SCV003718382	likely benign	Hereditary cancer-predisposing syndrome	2024-12-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000558882	SCV004015273	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-07-07	criteria provided, single submitter	clinical testing	A missense mutation was detected in the POLE gene in this specimen. This sequence change replaces valine with isoleucine at codon 1587 of the POLE protein (p.Val1587Ile). The valine residue is This variant is present in population databases (rs372388555, ExAC 0.02%). This variant has not been reported in the literature in individuals with POLE-related disease. ClinVar contains two entries for this variant both of which are listed as variant of unknown significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
PreventionGenetics, part of Exact Sciences	RCV004737825	SCV005365448	uncertain significance	POLE-related disorder	2024-06-05	no assertion criteria provided	clinical testing	The POLE c.4759G>A variant is predicted to result in the amino acid substitution p.Val1587Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/473692/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.