Submissions for variant NM_006231.4(POLE):c.1868A>G (p.Tyr623Cys)

gnomAD frequency: 0.00008  dbSNP: rs150564856

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482728	SCV000262379	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 623 of the POLE protein (p.Tyr623Cys). This variant is present in population databases (rs150564856, gnomAD 0.009%). 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: 221157). 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.
GeneDx	RCV000482728	SCV000570927	uncertain significance	not provided	2025-03-09	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 34355460, 20951805)
Ambry Genetics	RCV000561676	SCV000671283	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-28	criteria provided, single submitter	clinical testing	The p.Y623C variant (also known as c.1868A>G), located in coding exon 17 of the POLE gene, results from an A to G substitution at nucleotide position 1868. The tyrosine at codon 623 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was previously reported in the SNPDatabase as rs150564856. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.01% (1/8600) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.Y623C remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482728	SCV000889718	uncertain significance	not provided	2017-12-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763813	SCV000894730	uncertain significance	Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000206705	SCV001481202	uncertain significance	Colorectal cancer, susceptibility to, 12	2020-08-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469069	SCV002766317	uncertain significance	not specified	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: POLE c.1868A>G (p.Tyr623Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251436 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1868A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737332	SCV000806732	uncertain significance	POLE-related disorder	2024-06-12	no assertion criteria provided	clinical testing	The POLE c.1868A>G variant is predicted to result in the amino acid substitution p.Tyr623Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/221157/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.