Submissions for variant NM_006231.4(POLE):c.4724A>G (p.Tyr1575Cys)

gnomAD frequency: 0.00001  dbSNP: rs1008362127

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001766525	SCV000828488	uncertain significance	not provided	2024-12-04	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 1575 of the POLE protein (p.Tyr1575Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 577094). 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.
GeneDx	RCV001766525	SCV001991589	uncertain significance	not provided	2022-07-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000699763	SCV003807222	uncertain significance	Colorectal cancer, susceptibility to, 12	2022-11-29	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, PP3 supporting
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000699763	SCV004171488	uncertain significance	Colorectal cancer, susceptibility to, 12	2023-09-08	criteria provided, single submitter	clinical testing	The POLE c.4724A>G (p.Tyr1575Cys) missense change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV004944119	SCV005478810	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-06	criteria provided, single submitter	clinical testing	The p.Y1575C variant (also known as c.4724A>G), located in coding exon 36 of the POLE gene, results from an A to G substitution at nucleotide position 4724. The tyrosine at codon 1575 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.