Submissions for variant NM_006231.4(POLE):c.3670_3671delinsTT (p.Ala1224Leu)

dbSNP: rs864622698

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657100	SCV000261897	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1224 of the POLE protein (p.Ala1224Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 220928). 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. 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	RCV000657100	SCV000293690	uncertain significance	not provided	2024-07-09	criteria provided, single submitter	clinical testing	In silico analysis indicates that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236976	SCV000731427	uncertain significance	not specified	2017-01-12	criteria provided, single submitter	clinical testing	The p.Ala1224Leu variant in POLE has not been previously reported in individuals with colorectal cancer. This variant is a result of a deletion of 2 nucleotides at positions c.3670 and c.3671 and an insertion of two different nucleotides at these positions and is not predicted to alter the protein reading-frame. This v ariant has been identified in 5/66478 of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org, note that the ExAC data base reports this variant as 2 separate substitutions in cis, c.3670G>T [rs36933 8222] and c.3671C>T [rs375208564]). Computational prediction tools and conservat ion analysis suggest that the p.Ala1224Leu variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ala1224Leu variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657100	SCV001134713	uncertain significance	not provided	2018-10-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494537	SCV002775348	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	2022-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236976	SCV003933836	likely benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: POLE c.3670_3671delinsTT (p.Ala1224Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251358 control chromosomes (gnomAD), predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3670_3671delinsTT in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004943777	SCV005478838	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-06	criteria provided, single submitter	clinical testing	The c.3670_3671delGCinsTT variant (also known as p.A1224L), located in coding exon 30 of the POLE gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 3670 to 3671. This results in the substitution of the alanine residue for a leucine residue at codon 1224, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.