Submissions for variant NM_006231.4(POLE):c.6716C>T (p.Ala2239Val)

gnomAD frequency: 0.00006  dbSNP: rs190813054

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000759319	SCV000543955	uncertain significance	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2239 of the POLE protein (p.Ala2239Val). This variant is present in population databases (rs190813054, gnomAD 0.04%). 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: 405644). 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 expected to disrupt POLE protein function with a positive 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	RCV000759319	SCV000888573	uncertain significance	not provided	2018-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000759319	SCV001768320	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a pediatric patient with neuroblastoma (Zhang et al., 2015); Observed in the homozygous state in an individual with attenuated adenomatous polyposis and did not segregate with disease in the family (Lorca et al., 2019); This variant is associated with the following publications: (PMID: 23675308, 26580448, 31285513)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321599	SCV004027279	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000759319	SCV005197232	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005010338	SCV005634217	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	2024-06-04	criteria provided, single submitter	clinical testing
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000466959	SCV000844942	likely benign	Colorectal cancer, susceptibility to, 12	2018-06-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355812	SCV001550805	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The POLE p.Ala2239Val variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs190813054) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 13 of 276806 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: East Asian in 7 of 18868 chromosomes (freq: 0.000371), Latino in 4 of 34416 chromosomes (freq: 0.0001), European in 1 of 126374 chromosomes (freq: 0.00001), and South Asian in 1 of 30780 chromosomes (freq: 0.000032); it was not observed in the African, Other, Ashkenazi Jewish, and Finnish populations. The p.Ala2239 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. These computational analyses are not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.