Submissions for variant NM_006231.4(POLE):c.407A>T (p.Lys136Ile)

dbSNP: rs752771738

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001772268	SCV001218785	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 136 of the POLE protein (p.Lys136Ile). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 850323). 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 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.
GeneDx	RCV001772268	SCV002001960	uncertain significance	not provided	2022-12-14	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; Has not been previously published as pathogenic or benign to our knowledge
MGZ Medical Genetics Center	RCV001054469	SCV002579924	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-07-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002320299	SCV002628225	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The p.K136I variant (also known as c.407A>T), located in coding exon 5 of the POLE gene, results from an A to T substitution at nucleotide position 407. The lysine at codon 136 is replaced by isoleucine, an amino acid with dissimilar 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321790	SCV004027379	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001772268	SCV004184296	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing